Colon Cancer, Chemotherapy, & Antioxidants
BY JOHANNA ALTGELT, HELEN LEE, and MICHAEL McCULLOCH
In the previous three issues of Avenues, we reported on the use of antioxidants
along with chemotherapy as they apply to prostate, breast, and lung cancer
patients. In this issue, we turn our focus to colon cancer.
In most cases, colon cancer treatment involves chemotherapy. However,
toxicity and tumor cell drug resistance are notable drawbacks to this
treatment.
Although not commonly addressed in clinical consultation, scientific
evidence suggests that combining certain chemotherapy treatments with
specific antioxidants at defined dosages can improve drug effectiveness
or may reduce side effect severity.
This issue is important because it has long been the opinion of most
practicing oncologists that antioxidants should not be used concurrently
with chemotherapy as it was believed that the combination might inhibit
chemotherapy effectiveness. This reluctance stems, in part, from the
fact that some chemotherapy drugs work by strongly promoting oxidation.
This is especially the case for the class of chemotherapy drugs called
anthracyclines (Adriamycin and epirubicin), the alkylating agents (chlorambucil,
cyclophosphamide, thiotepa, and busulfan), and the platinum drugs (cisplatin
and carboplatin). Antioxidants, by definition, inhibit oxidation, so
it was believed that antioxidants would prevent these chemotherapy
drugs from working properly.
The controversy around using antioxidants together with chemotherapy
is not based on many studies that show an adverse effect of adding antioxidants
to chemotherapy. Rather this controversy is based on several studies
that show how depleting glutathione, which is a natural antioxidant
in the body, can enhance the treatment effect of chemotherapy. (Meijer,
Mulder et al. 1990; Mans, Schuurhuis et al. 1992; Doyle, Ross et al.
1995; Versantvoort, Broxterman et al. 1995; Zaman, Lankelma et al.
1995; Kurokawa, Nishio et al. 1997; Lee, Park et al. 2004) Although
this has led many oncologists to believe that this means all antioxidants
should not be combined with chemotherapy, there are numerous laboratory
and human studies showing how combining chemotherapy with antioxidants
can indeed be helpful.
In this systematic review, we searched for every paper on the combination
of antioxidants and chemotherapy in colon cancer and found only one laboratory
(and no human) studies demonstrating a harmful effect, which was the
combination of the antioxidant N-acetyl cysteine with paclitaxel. (Alexandre,
Nicco et al. 2006)
Chemotherapy drugs that cause high levels of “oxidative stress” are
thought to rely in part on oxidative stress to kill cancer cells, but
other effects of that oxidative stress may also be getting in the way
of the effectiveness of the chemotherapy. This is because oxidative stress
slows cell replication. However, chemotherapy relies on fast cancer cell
replication to be effective because it is during the moment of cell replication
that chemotherapy kills cancer cells. (Conklin 2000) One approach to
addressing this problem is the addition of certain antioxidants at specific
dosages to lessen oxidative stress, thus making the chemotherapy treatment
more effective (Perumal, Shanthi et al. 2005).
The interaction between chemotherapy and antioxidants is more complex
than simply promoting and inhibiting oxidative stress. There are several
mechanisms by which chemotherapy drugs function and antioxidants also
have a number of different effects on the body. Each antioxidant has
a different interaction with chemotherapy and this effect can change
based upon the dosage used. Because the chemotherapy-antioxidant debate
often focuses almost exclusively on oxidative stress, in this paper
we broaden that discussion to include the many mechanisms by which
antioxidants help in the fight against colon cancer.
The question is really not whether antioxidants should be used in combination
with chemotherapy but rather which should be used and at what dosages.
PURPOSE OF THIS PAPER
In this evidence-based review article, we discuss the results of current
research showing how antioxidants may enhance or, in some cases, inhibit
the therapeutic action of specific chemotherapy drugs used in the treatment
of colon cancer. Some of these antioxidants may also reduce chemotherapy
side effects or inhibit chemotherapy resistance in colon cancer cells.
Finally, some of these antioxidants have been found to be useful for
restoring the natural antioxidants in the body, which are often depleted
after the completion of chemotherapy.
HOW NUTRIENT DEPLETION FROM CHEMOTHERAPY CAN OCCUR
Chemotherapy can cause nutrient depletion from two major side effects.
One is nausea and vomiting, making it more difficult for the patient
to maintain adequate nutrient intake. Another is toxicity to cells
in the gastrointestinal tract, making it more difficult for the intestines
to adequately absorb nutrients. Antioxidants are not the only nutrients
to become depleted; vitamins, minerals, amino acids, and fatty acids
may also be compromised, especially in patients who have suffered these
side effects for a prolonged amount of time.
METHODS
We searched for clinical or laboratory data published in peer-reviewed
medical journals, conducted by cancer researchers in universities and
medical research facilities around the world. Some of these studies
are still in early stages and include only laboratory or animal data
while others have advanced to include human volunteers.
We organized these data into the major categories of specific chemotherapy
drugs. Within each section for a specific drug are found the research
on combinations of that drug with various antioxidants, grouped by the
name of the antioxidant in alphabetical order. We also point out specifically
which studies were conducted in a laboratory (i.e. using cancer cell
cultures), which were conducted using animals, and which were conducted
with human volunteers. As each antioxidant appears in the paper for the
first time, we provide some introduction to the antioxidant including
what food sources naturally contain it, other common applications in
clinical use, and typical dosages. The dosages given are not necessarily
appropriate for all patients and should be individualized with practitioner
guidance.
MECHANISMS OF ANTIOXIDANTS IN CANCER THERAPY
There are various mechanisms by which antioxidants play a roll in cancer
therapy.
AMP-activated protein kinase (AMPK)
AMPK is an enzyme that helps inhibit the growth of some cancers (including
colon cancer) when it is activated. AMPK can be activated by exercise
and fasting, and by genes that suppress tumors. (Shaw, Kosmatka et al.
2004; Luo, Saha et al. 2005)
Antioxidants that are known to activate AMPK and suppress growth of
colon cancer include genistein (Hwang, Ha et al. 2005), green tea or
the compound found in green tea called EGCG, (Hwang, Ha et al. 2007)
selenium, (Hwang, Kim et al. 2006) and capsaicin, which is found in chili
peppers. (Kim, Hwang et al. 2007)
BCL-2 Family
The proteins in the BCL-2 family can determine whether a cell lives or
dies. The following are proteins in this family:
1) BCL-2 and BCL-XL are proteins that promote cell survival.
2) BH3-only proteins can sense stress in a cell and can send a signal
for the cell to die.
3) Bax and Bak are proteins that, when activated, lead to cell death.
In the development of colon cancer, there are frequently mutations in
the genes encoding for Bax. (Rupnarain, Dlamini et al. 2004; Woerner,
Kloor et al. 2005; Fernandez-Luna 2007; Adams and Cory 2007)
The antioxidant genistein activates Bax. (Hwang, Ha et al. 2005) While
the antioxidants N-acetyl cysteine and vitamin E and the chemotherapy
agent 5-fluorouracil do not activate Bax when used alone, when either
antioxidant is combined with 5-fluorouracil, Bax expression doubles,
meaning that the combination is superior to chemotherapy used alone.
(Adeyemo, Imtiaz et al. 2001)
Caspase-3
Caspase-3 is an enzyme that promotes cell death. (Porter and Janicke
1999) The above-mentioned activation of Bax and Bak (from the BCL-2 family)
precede activation of caspases such as caspase-3. (Fernandez-Luna 2007)
Increase in caspase-3 activation in colon cancer cells may be caused
by antioxidants such as curcumin, (Jaiswal, Marlow et al. 2002) diallyl
sulfide (from garlic), (Sriram, Kalayarasan et al. 2008) and the synthetic
antioxidant edavarone. (Kokura, Yoshida et al. 2005) Increasing caspase-3
activation means that this enzyme can help control cancer cell growth.
Cyclooxygenase-2 (COX-2)
COX-2 is an enzyme that is involved in the development of colon cancer.
COX-2 is also involved in resistance to cell death. COX-2 is correlated
with angiogenesis and tumor growth and metastasis. Note that COX-2 is
also correlated with normal angiogenesis, such as wound healing. For
colon cancer patients, it is beneficial to inhibit COX-2. For example,
long-term use of COX-2 inhibitors, which are non-steroidal anti-inflammatory
drugs (NSAIDS) such as aspirin, decreases the risk of colorectal cancer
and can regress colorectal polyps in patients with familial adenomatous
polyposis. (Bakhle 2001; Sinicrope 2006)
Examples of antioxidants that inhibit COX-2 in colon cancer include curcumin,
(Du, Jiang et al. 2006) genistein, (Hwang, Ha et al. 2005) n-3 PUFA from
fish oils, and EGCG from green tea. (Hwang, Ha et al. 2007)
c-Myc
c-Myc is a protein that plays an essential role in the regulation of
healthy cell growth. Misregulation of this protein occurs in many cancers
including colon cancer. (Wierstra and Alves 2008; Robson, Pelengaris
et al. 2006)
Curcumin can suppress colon cancer by regulating c-Myc activity. (Jaiswal,
Marlow et al. 2002) DHA from fish oil together with 5-fluorouracil can
cause colon cancer cell death, which involves c-Myc protein regulation.
(Calviello, Di Nicuolo et al. 2005)
Growth Factor Receptors
Epidermal growth factor receptor (EGFR), human epidermal growth factor
receptor (HER-2), and insulin-like growth factor 1 receptor (IGF-1R)
are all receptors that are involved in normal cell division and growth.
However, when genetic mutations lead to overexpression or overactivity,
they are associated with uncontrolled cell division and cancer. (Sibilia,
Kroismayr et al. 2007) New cancer therapies are being developed that
target these receptors. (Press and Lenz 2007) Cetuximab (Erbitux) is
one of these new therapies used in the treatment of metastatic colorectal
cancer and this drug works by inhibiting EGFR. The antioxidant curcumin
decreases expression and activation of EGFR, HER-2, and 1GF-1R. (Patel,
Sengupta et al. 2008)
Glucose Transporter Protein 1 (Glut-1)
Glut-1 is a transporter protein that transports glucose into tissues.
It is present in normal cells, but is overly expressed in tumors because
tumors require more glucose to meet their increased metabolic needs.
In colorectal cancers, expression of Glut-1 has been associated with
decreased survival time and more advanced tumors. (Fogt, Wellmann et
al. 2001)
The antioxidants EGCG from green tea (Hwang, Ha et al. 2007) and genistein
from soy (Hwang, Ha et al. 2005) both decreased Glut-1 in colon cancer
cells.
Glutathione S-transferase pi (GSTpi)
GSTpi is part of a family of glutathione S-transferase. Low glutathione
S-transferase has been correlated with colon cancer risk. Glutathione
S-transferase levels can be increased by eating fruits and vegetables
(Grubben, Nagengast et al. 2001) and curcumin. (Chauhan 2002)
Conversely, GSTpi has also been associated with doxorubicin chemotherapy
resistance in colon cancer cells. (Takahashi and Niitsu 1994) Lower levels
of GSTpi allow doxorubicin to more effectively kill colon cancer cells.
Agaricus bisporus lectin, found in the ordinary white button mushroom,
is an inhibitor of GSTpi and can increase the effectiveness of several
chemotherapy agents in colon cancer. (Goto, Kamada et al. 2002)
Nuclear factor kappa B (NF-kappaB)
Activation of NF-kappaB, a protein complex, is not favorable in cancer
treatment. It leads to cellular events that promote inflammation, cell
proliferation, angiogenesis, metastasis, and discourages cell death.
NF-kappaB is associated with cancer risk, poor prognosis, and contributes
to chemotherapy resistance. (Lee, Jeon et al. 2007; Sethi, Sung et al.
2008)
NF-kappaB is activated by many chemotherapeutic compounds and is also
inhibited by antioxidants including curcumin, (Hatcher, Planalp et al.
2008) the synthetic antioxidant edavarone, (Kokura, Yoshida et al. 2005)
and saponins extracted from ginseng. (Choo, Sakurai et al. 2008) Although
diallyl sulfide extracted from garlic increases expression of NF-kappaB,
it also showed strong inhibition of cancer cell growth. (Sriram, Kalayarasan
et al. 2008)
p53 and p21
p53 is a protein our cells can produce to help suppress the growth of
tumors, including colon cancer, and often becomes activated when the
DNA has mutations. However, viruses or even other genes can inactivate
p53. The gene encoding for p53 may be mutated, particularly in families
with a high incidence of cancer, leaving cells more vulnerable to unregulated
growth.
p21 is a related protein that is activated by p53 and is also involved
in suppressing tumor growth. (Maddika, Ande et al. 2007)
Activation of p53 and p21 in colon cancer has been demonstrated with
genistein from soy (Hwang, Ha et al. 2005) and vitamin E. (Chinery, Brockman
et al. 1997)
Prostaglandins
Prostaglandins, a group of hormone-like chemicals, promote colon cancer
cell growth and are generated by Cox-2 (see Cox-2 on previous page).
(Pai, Nakamura et al. 2003)
EGCG from green tea, (Hwang, Ha et al. 2007) genistein from soy (Hwang,
Ha et al. 2005) and selenium (Hwang, Kim et al. 2006) can all decrease
prostaglandins.
Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor (VEGF) is an important protein involved
in developing a new blood supply such as vasculogenesis (formation of
new blood vessels when there are no pre-existing ones) and angiogenesis
(formation of new blood vessels from pre-existing ones). In the case
of cancer, most tumors require a more extensive blood supply to bring
nutrition to support rapid growth. (Veeravagu, Hsu et al. 2007)
EGCG from green tea decreases VEGF. (Hwang, Ha et al. 2007)
5-Fluorouracil
ALPHA-MANGOSTIN
Alpha-Mangostin is a compound found in the pericarp (the tissue surrounding
the seed) of the mangosteen fruit. Mangosteen is a tropical evergreen
tree that originates from the Malay Archipelago between mainland Southeastern
Asia and Australia. Alpha-Mangostin is a powerful antioxidant and has
antibiotic, antiviral, and anti-inflammatory activity.
» Mangosteen: Typical doses of mangosteen extract (in capsule
or juice form) range from 400 mg to 60,000 mg per day.
In a laboratory study, when alpha-mangostin was combined with 5-fluorouracil
(at a concentration of 2.5 µM each), the growth suppression of
human colon cancer cells was significantly stronger than 5-fluorouracil
treatment alone (at a higher dose of 5 µM). (Nakagawa, Iinuma
et al. 2007)
AVEMAR
Avemar is a fermented wheat germ extract developed in Hungary. It supports
healthy immune function, inhibits cell proliferation and cell adhesion,
enhances apoptosis, and has antioxidant activity.
» Avemar: For an adult of average weight (approximately 155 lbs),
a typical daily dose is 9 g, ideally one hour before eating. Patients
with a body weight of 200 lbs or more should consume two 9 g doses
per day, ideally one hour before breakfast and dinner.
In an animal study using mice with colon cancer, avemar significantly
enhanced the anti-metastatic effect of 5-fluorouracil and dacarbazine.
Combined treatment decreased toxicity such as weight loss compared to
chemotherapy agents administered alone. (Hidvegi, Raso et al. 1999)
CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice
plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid,
and anti-inflammatory properties. It also promotes healthy bile excretion
and healthy platelet function.
» Curcumin: The best supplements contain curcumin at 75% or higher
concentration. Typical doses range from 500 mg to 2,000 mg daily. Take
with meals, as curcumin can cause stomach upset when taken on an empty
stomach. Bioavailability and potency are increased when combined with
bioperine, an extract from black pepper.
In a laboratory study, curcumin was used in combination with 5-fluorouracil
in the treatment of human colon cancer cells. This combination proved
synergistic. Additionally, COX-2 protein expression was reduced almost
six-fold in the combined treatment. (Du, Jiang et al. 2006)
A second laboratory study confirmed the same finding, that curcumin in
combination with 5-fluorouracil markedly inhibited the growth of colon
cancer cells in comparison to 5-fluorouracil alone. (Kim, Park et al.
2005)
D-GLUCARATE
D-glucarate is a botanical extract from grapefruit, apples, oranges,
broccoli, and brussel sprouts. It supports the internal detoxification
system called glucuronidation, which makes foreign substances easier
to remove from the body. For dietary supplementation, it is combined
with calcium to form calcium d-glucarate.
» Calcium D-glucarate: Typical doses range from 50 to 1,000 mg
per day.
In a laboratory study with colon tumors from rats, 5-fluorouracil was
combined with D-glucarate, which enhanced its effectiveness. (Schmittgen,
Koolemans-Beynen et al. 1992)
DIALLYL DISULFIDE (DADS)
Diallyl disulfide (DADS) is a major organosulfur compound found in garlic
(Allium sativum) oil.
» Garlic: Typical doses range from 5 to 15 grams per day of
whole, fresh garlic and 4,000 to 8,000 micrograms per day of allicin
extract.
In an animal study, DADS did not change the effectiveness of 5-fluorouracil
treatment in mice with colon tumors. However, the combined treatment
significantly reduced chemotherapy-induced side effects such as depressed
leukocyte counts, decreased spleen weight, and elevated plasma urea.
(Sundaram and Milner 1996)
DOCOSAHEXAENOIC ACID (DHA)
Omega-3 fatty acids come from several different sources and in several
different forms. Sources include blue-green algae, fish oil, and eggs.
The most active in cancer care are docosahexaenoic acid (DHA) and eicosapentaenoic
acid (EPA). It is used as a supplement in clinical practice for many
therapeutic uses, some of which include cancer, heart disease, depression,
diabetes, and multiple sclerosis.
» Omega 3 Polyunsaturated fatty acids (PUFA, from fish oil
including DHA/EPA): Typical dosage range is from 1,000 mg to 10,000 mg daily.
When finding a fish oil supplement, it is important to identify brands
that can provide assurance that they’ve tested for heavy metals
such as mercury.
DHA enhances colon cancer cell death of four different cell lines together
with 5-fluorouracil according to a laboratory study. Concentrations of
5-fluorouracil and DHA used in the study were lower than concentrations
typically achieved in patients who are treated with these two agents.
5-fluorouracil inhibited BCL-2 and BCL-XL (types of proteins that enhance
tumor cell growth) and induced overexpression of c-Myc. DHA markedly
increased these effects, working synergistically with 5-fluorouracil.
(Calviello, Di Nicuolo et al. 2005)
EICOSAPENTAENOIC ACID (EPA)
In an animal study using mice, EPA increased the tumor growth inhibition
by 5-fluorouracil. It also prevented weight loss normally induced by
5-fluorouracil. (Wynter, Russell et al. 2004)
EPIGALLOCATECHIN-3-GALLATE (EGCG) & GREEN TEA
EXTRACT
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in
green tea.
» EGCG: One cup of green tea contains between 10 and 400 mg of
polyphenols depending on the source, amount of leaves used, and steeping
time. EGCG may be conveniently obtained from extracts. A good product
contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.
In a laboratory study, EGCG in combination with 5-fluorouracil or etoposide,
reduced colon cancer cell growth more effectively than either 5-fluorouracil
or etoposide alone. This study found that EGCG strongly activated AMPK
(an enzyme that helps inhibit the growth of some cancers), inhibited
COX-2, decreased VEGF (vascular endothelial growth factor), and the glucose
transporter Glut-1. (Hwang, Ha et al. 2007)
In a case report series, seven patients with familial polyposis underwent
surgery and then received follow up preventive treatment with 5-fluorouracil
suppositories and green tea extract. No rectal cancer developed in any
of these patients. (Ichikawa, Takahashi et al. 1998)
FISH OIL (DHA/EPA)
In a laboratory study using colon cancer cells, the combined treatment
of 5-fluorouracil with fish oil-based lipid emulsion led to significantly
more growth inhibition when compared to either treatment alone. (Jordan
and Stein 2003)
» Fish Oil: Typical dosages of fish oil range from 1,000 mg to
10,000 mg daily.
GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones
are antioxidants that counteract the damaging effects of free radicals
in body tissues. Isoflavones, such as genistein, also have anti-angiogenic
effects, blocking the formation of new blood vessels needed to support
the growth of tumors.
» Genistein: A good product will use organic non-GMO genistein.
To achieve anti-tumor effects, the target daily dose, based on animal
studies and calculations for similar human dosage, is 1500 mg. The
recommended dose for furtherresearch is between 100 mg and 1100 mg. (Boik
2001) One cup of soy milk will contain on average about 45 mg of genistein
and the other related isoflavones.
When genistein was used together with 5-fluorouracil in the treatment
of colon cancer cells in a laboratory study, cell death of colon cancer
cells was significantly increased when compared to 5-fluorouracil alone.
Investigating the mechanism of this synergistic combination revealed
increased activation of AMPK, up-regulation of p53, p21, and Bax, as
well as abrogation of the up-regulated state of COX-2 and Glut-1 normally
induced by 5-fluorouracil, all of which are ideal for maximum treatment
effect. (Hwang, Ha et al. 2005)
GLUTAMINE
Glutamine is a nonessential amino acid. It is necessary for rapidly dividing
cells including the intestines and immune system.
» Glutamine: Typical doses range from 500 to 1000 mg per day.
A double blind, randomized controlled trial was conduced to assess whether
oral glutamine could prevent intestinal complications of treatment with
5-fluorouracil and folinic acid. Seventy colorectal patients who had
not received any chemotherapy prior to the study were enrolled and received
either chemotherapy with placebo or chemotherapy with 18 g per day of
oral glutamine. Glutamine treatment started five days prior to the beginning
of chemotherapy and continued for fifteen days after completion of chemotherapy.
The study only covered one chemotherapy cycle, which was given daily
for five days.
The reduction of intestinal absorption was more marked in the placebo
group and reduction of intestinal permeability was also higher in the
placebo group. Average diarrhea was less in the glutamine group and also
did not last as long. In the placebo group, one patient developed grade-4
diarrhea (defined as physiological consequences requiring intensive care
or haemodynamic collapse) while no patients in the glutamine group developed
grade-4 diarrhea. Patients were instructed to take loperamide tablets
upon experiencing diarrhea. Patients in the glutamine group consumed
less loperamide tablets than the placebo group. This trial thus demonstrated
that glutamine protected intestinal mucosa from chemotherapy induced
damage. (Daniele, Perrone et al. 2001)
GLUTATHIONE
Glutathione is one of the most powerful and important natural antioxidants
produced in the body.
» Glutathione: Typical dosage ranges between 50 mg and 600 mg
daily. N-acetyl cysteine is the pre-cursor of glutathione and is more
efficiently absorbed. When taking Glutathione or N-acetyl cysteine,
combine with three times as much vitamin C. Vitamin C prevents these
amino acids from being oxidized in the body and ensures their ability
to act as antioxidants.
In a clinical trial with 33 gastric cancer patients and 17 colon cancer
patients, intravenous glutathione (1,200 mg per day) was tested in combination
with 5-fluorouracil, FT-207 (a different configuration of fluorouracil),
and tegafur suppositories. In gastric cancer patients who received glutathione,
5-fluorouracil concentrations in tumors were significantly higher than
in patients who did not receive glutathione. However, this effect was
not observed in colon cancer patients. (Kitajima, Ikeda et al. 1987)
A laboratory study found that cellular glutathione levels naturally became
elevated in human colon cancer cells exposed to 5-fluorouracil for 24
hours. The study found that pretreatment of cancer cells with 5-fluorouracil
enhanced the uptake of methotrexate and suggested that the increase in
glutathione may have a role in the enhanced methotrexate uptake and cytotoxicity
of both chemotherapy drugs. (Chen, Chen et al. 1995)
LENTINAN
Lentinan is a polysaccharide derived from the edible Japanese shiitake
mushroom. It possesses immunostimulating antitumor properties.
» Shiitake mushroom extracts: Typical doses range from 100 to
400 mg per day.
In a randomized controlled trial testing lentinan in combination with
5-fluorouracil and mitomycin C or tegafur, a survival advantage was found
in advanced or recurrent gastrointestinal cancer patients receiving lentinan.
This effect was significant in gastric cancer patients. In colorectal
cancer patients, there was also a survival advantage. (Taguchi, Furue,
et al. 1985)
N-ACETYL CYSTEINE
N-acetyl cysteine is an efficiently absorbed and used form of the amino
acid, L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three
amino acids that form glutathione, which is one of the most important
and powerful antioxidants in the body.
» N-acetyl cysteine: Typical dosages range between 600 and 1,800
mg per day.
In a laboratory study, N-acetyl cystine augmented apoptosis in combination
with 5-fluorouracil in colorectal cancer cell lines. This study found
a possible mechanism with induced expression of the pro-apoptotic protein
Bax in the treatment combining the two therapies. It was found that neither
5-fluorouracil nor N-acetyl cysteine alone induced an increase in Bax
expression, however when combined, Bax expression doubled. (Adeyemo,
Imtiaz et al. 2001)
NOTOGINSENG FLOWER EXTRACT
Also known as tianqi and sanqi, notoginseng is a very commonly used Chinese
herb for regulating the blood, improving immune function, decreasing
fatigue, and improving cognitive, sexual and physical performance.
» Notoginseng: Typical doses range between 250 mg and 1,500 mg
daily.
In a laboratory study, notoginseng flower extract significantly increased
the anti-proliferation effect of 5-fluorouracil in human colorectal cancer
cells. Used as a single agent, 5-fluorouracil inhibited the growth of
colon cancer cells by 31.1% and when combined with the notoginseng flower
extract, this effect was increased to 59.4%. (Wang, Luo et al. 2007)
URIDINE
Uridine is a nucleoside that can be extracted from sugarcane.
» Uridine: A supplement called NucleomaxX contains 6 g of nucleosides
(including uridine) from an extract of sugarcane. The recommended dose
is 3 sachets per day, dissolved in water for three consecutive days,
once every month.
An animal study used mice with colon cancer both sensitive and resistant
to 5-fluorouracil that were treated with the chemotherapy agents 5-fluorouracil
and leucovorin. Treatment with uridine (3,500 mg per kg) allowed the
use of higher doses of 5-fluorouracil, which improved the antitumor effect
on mice that had tumors resistant to 5-fluorouracil. (Nadal, van Groeningen
et al. 1989)
VITAMIN E
Vitamin E includes several related compounds: Tocopherols and tocotrienols,
each of which have four subtypes of alpha, beta, gamma, and delta. Previously,
only alpha-tocopherol was considered important, however each type has
unique contributions to health. The best dietary sources of vitamin E
are considered to be unrefined, cold-pressed vegetable oils (such as
wheat germ, sunflower seed, and olive oils) and raw or sprouted seeds,
nuts, and grains.
» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol
or succinate. Seek out the mixed tocopherols, including tocopherols
and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.
In a laboratory study, vitamin E augmented apoptosis in combination with
5-fluorouracil in colorectal cancer cell lines. This study found a possible
mechanism with induced expression of the pro-apoptotic protein named
Bax in the treatment combining the two therapies. It was found that neither
5-fluorouracil nor vitamin E alone induced an increase in Bax expression,
however when combined, Bax expression doubled. (Adeyemo, Imtiaz et al.
2001)
In a laboratory and animal study, the combination of vitamin E and 5-fluorouracil
significantly enhanced colorectal cancer tumor growth inhibition in vitro
and in vivo. The mechanism by which vitamin E caused apoptosis was by
induction of p21, a powerful inhibitor of the cell cycle. (Chinery, Brockman
et al. 1997)
Cyclophosphamide
EICOSAPENTAENOIC ACID (EPA)
In an animal study using mice, EPA from fish oil increased the tumor
growth inhibition by cyclophosphamide. (Wynter, Russell et al. 2004)
FOLFOX
CURCUMIN
In a laboratory study, curcumin significantly enhanced the inhibition
of growth in two different colon cancer cell lines in combination with
the FOLFOX chemotherapy regimen. FOLFOX chemotherapy includes leucovorin,
5-fluorouracil, and oxaliplatin. The combination treatment with curcumin
decreased activation and expression of epidermal growth factor receptor
(EGFR), HER-2 (also known as ErbB-2), and insulin-like growth factor-1
receptor (IGF-1R) and their downstream effectors Akt and cycloxygenase-2.
(Patel, Sengupta et al. 2008)
GOSHAJINKIGAN (NIU CHE SHEN QI WAN)
Goshajinkigan is the Japanese name (Niu Che Shen Qi Wan is the Chinese
name) for an herbal formula that is used in the treatment of diabetic
neuropathy. In a case report from Japan, a 57-year-old woman with advanced
stage IV colon cancer underwent surgery and after the operation was given
the chemotherapy regimen called FOLFOX 6. The patient took two courses
of chemotherapy and grade-2 neurotoxicity developed. The patient was
then given the goshajinkigan herbal formula from the third chemotherapy
course and the severity of neurotoxicity reduced to grade-1. (Mamiya,
Kono et al. 2007)
Gemcitabine
DOCOSAHEXAENOIC ACID (DHA) & EICOSAPENTAENOIC
ACID (EPA)
In an animal study using mice, EPA and DHA had no effect on the antitumor
effect of gemcitabine. (Wynter, Russell et al. 2004)
Interleukin-2
MELATONIN
Melatonin is a hormone that is released from the pineal gland in the
evening and promotes normal sleep; its secretion diminishes significantly
with age. It is known to help maintain cell health and many people take
it to improve sleep. It is also known to reduce metastasis in cancer
patients. In most published studies, melatonin shows a beneficial effect,
although it has been reported that in a small proportion of people, melatonin
can paradoxically cause sleep disturbance. In others, there can be residual
daytime drowsiness, which is usually resolved by using a lower dose.
» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming
for a high dosage, one should start with 1 mg and increase the dosage
slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood
levels of melatonin at about 2am. To do so, one can take the melatonin
at bedtime, ideally between 9pm and 10pm.
A clinical trial included 50 metastatic colorectal cancer patients who
either had progressed or did not respond to treatment with 5-fluorouracil
and folates. Patients were randomized to receive either interleukin-2
(3 million IU per day subcutaneously for 6 days a week for 4 weeks) and
melatonin (40 mg per day orally) or supportive care. A partial response
was achieved in 3 out of 25 patients treated with interleukin-2 and melatonin
whereas no tumor regression occurred in patients receiving only supportive
care. Survival at one year was significantly higher in patients treated
with interleukin-2 and melatonin (9 out of 25) in comparison to patients
receiving only supportive care (3 out of 25). (Barni, Lissoni et al.
1995)
Another clinical trial enrolled 14 metastatic colorectal cancer patients
pretreated with 5-fluorouracil. Patients were given low dose interleukin-2
(3 million IU per day for 6 days a week once per day subcutaneously for
4 weeks) with melatonin (50mg per day orally at 8pm). Thirteen patients
were evaluable: no tumor regression was seen and stabilized disease was
achieved in four patients for a median duration of five months. The other
nine patients progressed. (Barni, Lissoni et al. 1992)
Irinotecan
AGARICUS BISPORUS LECTIN
Agaricus bisporus lectin is the active component found in the table mushroom
or button mushroom, one of the most widely cultivated mushrooms in the
world.
In a laboratory study, agaricus bisporus lectin increase the sensitivity
of human colon cancer cells to the treatment of irinotecan, cisplatin,
and doxorubicin. No effect was observed when combined with etoposide
and 5-fluorouracil. The mechanism thought to underlie this synergism
was that agaricus bisporus lectin is an inhibitor of the nuclear transport
of glutathione S-transferase (GST) pi. GST pi was found to accumulate
in cancer cells in response to chemotherapy and may contribute to drug
resistance. (Goto, Kamada et al. 2002)
EDAVARONE
Edavarone is a synthetic antioxidant. We report its use here to demonstrate
how pharmaceutical companies are investigating antioxidants (that can
be patented) in combination with chemotherapy, while physicians continue
warning about natural antioxidant use.
» Edavarone: Edavarone (trade name Radicut) is a free-radical
scavenger manufactured in Japan and used primarily in the treatment
of acute stroke.
In a laboratory study, edaravone enhanced the treatment effect of irinotecan
in human colon cancer cells. The mechanism included inhibition of NF-kappaB
and also enhanced activation of caspase-3. Irinotecan also activated
caspase-3 and in contrast to edaravone activated NF-kB. Edaravone scavenged
the reactive oxygen species induced by irinotecan and, according to conventional
wisdom and the current stance on antioxidants in combination with chemotherapy,
this should mean edavarone would decrease treatment effect of ironotecan.
To the contrary, however, the combination is synergistic, meaning there
was a beneficial enhancement of the therapeutic effect of irinotecan.
The study continued in vivo, where irinotecan combined with edaravone
reduced subcutaneous tumor growth and pulmonary metastases more than
irinotecan treatment alone. (Kokura, Yoshida et al. 2005)
MELATONIN
A clinical trial investigated combined treatment of irinotecan and melatonin.
Thirty metastatic colorectal cancer patients, who had progressed after
at least one chemotherapy treatment including 5-fluorouracil, were randomized
to treatment with irinotecan alone or irinotecan (125 mg per m2 weekly,
administered intravenously) plus melatonin (20 mg per day taken orally,
in the evening) for nine consecutive weeks of treatment. There was no
complete response. Partial responses occurred in 2 out of 16 patients
receiving ironotecan alone and in 5 out of 14 patients also receiving
melatonin. Stable disease occurred in 5 out of 16 patients receiving
ironotecan alone and in 7 out of 14 patients also receiving melatonin.
Disease control in patients receiving ironotecan alone was 7 out of 16
and 12 out of 14 in patients also receiving melatonin. This is a significantly
higher percentage of disease control for patients receiving a combination
of ironotecan and melatonin. Diarrhea of grade 3-4 occurred in 6 out
of 16 patients treated with irinotecan alone and in 4 out of 14 patients
treated with irinotecan plus melatonin and required a 50% dose reduction.
Disease control was similar in patients who received full dose of chemotherapy
and those receiving a reduced dose. (Cerea, Vaghi et al. 2003)
SELENIUM
Selenium is an essential trace mineral in the body and is found in variable
amounts in food depending on the soil content of selenium. Brazil nuts
are the single best food source of selenium. One of its roles in the
body is as an antioxidant and it is most widely known as a cancer preventive.
» Selenium (mineral): The US adult Tolerable Upper Intake Level
(UL) is 400 micrograms a day and the Lowest Observed Adverse Effects
Level (LOAEL) for adults is about 900 micrograms daily. There are several
different forms of selenium. Se-Methylselenocysteine is a highly bioavailable
form because it is not incorporated within a protein such as the form
selenomethionine. We recommend getting selenium either in the organically
bound forms such as of Se-Methylselenocysteine or a combination of
selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione,
and Se-methylselenocysteine.
An animal study using mice with colon cancer types that are sensitive
and resistant to chemotherapy tested the selenium compounds 5-methylselenocysteine
and seleno-L-methionine together with various chemotherapy agents including
irinotecan. Selenium was highly protective against toxicity induced by
various chemotherapy agents including 5-fuorouracil, cisplatin, oxaliplatin,
paclitaxel, and doxorubicin. The effect of selenium on treatment effectiveness
was measured only with irinotecan. In combination with the maximum tolerated
dose of irinotecan, selenium (administered seven days prior to chemotherapy
and continuing throughout chemotherapy treatment) significantly increased
the cure rates of mice with colon cancer tumors that are sensitive and
resistant to irinotecan. For example, in tumors resistant to irinotecan
treatment with ironotecan alone lead to a cure rate of 0%. When combined
with selenium, the cure rate rose to 20%. In tumors that were sensitive
to ironotecan, whereas treatment with ironotecan alone showed a cure
rate of 20%, irinotecan combined with selenium showed a cure rate of
an astonishing 100%. Selenium combined with chemotherapy treatment was
also effective in preventing weight loss. (Cao, Durrani et al. 2004)
Oxaliplatin, 5-Fluorouracil, and Leucovorin
CALCIUM GLUCONATE & MAGNESIUM SULFATE
Calcium gluconate is a mineral that is found naturally in foods such
as almonds, sesame seeds, dark green leafy vegetables, milk, and yogurt.
Calcium (Ca) is needed for many bodily functions, especially bone formation.
Calcium can bind to other minerals and aid in removal from the body.
Calcium gluconate is used to prevent and treat calcium deficiencies.
Magnesium (Mg) is a mineral that is present in many foods, including
almonds, cashews, soybeans, buckwheat, and wheat bran. Magnesium helps
maintain normal nerve and muscle function, keeps the heart rhythm steady,
keeps bones strong, and supports the immune system. Magnesium sulfate
is one form of magnesium supplements.
A retrospective cohort study from France included 161 colorectal cancer
patients. 65 patients received chemotherapy alone and 96 patients received
intravenous infusions of calcium gluconate and magnesium sulfate (1 g
each) delivered over 15 minutes prior to chemotherapy. Chemotherapy treatment
consisted of oxaliplatin, 5-fluorouracil, and leucovorin. The FOLFOX
4 regimen (oxaliplatin 85 mg per m2 every two weeks), FOLFOX 6 (oxaliplatin
100 mg per m2 every two weeks), and FUFOX (130 mg per m2 every three
weeks) were used. Tumor response and toxicity were evaluated. Treatment
efficacy was evaluated three months after the beginning of treatment.
The number of patients receiving FUFOX regimen were similar, 42 receiving
CaMg and 43 receiving chemotherapy alone. The other regimens had unequal
numbers of patients either receiving CaMg or not, therefore this study
only collected data on treatment efficacy in the FUFOX group.
Treatment efficacy: Both the number of treatment cycles and the mean
cumulative oxaliplatin doses were higher in patients treated with CaMg
compared to patients receiving chemotherapy alone, however the difference
was not statistically significant. After 12 cycles of chemotherapy, the
percentage of patients remaining in treatment was greater in patients
receiving CaMg. This was seen most pronounced in patients receiving the
FOLFOX 6 regimen where 36% of patients remained receiving CaMg and 11%
remained receiving chemotherapy alone. The response rate was 45% in patients
receiving CaMg and 35% in patients receiving chemotherapy alone.
No CaMg induced toxicity was observed. At the end of treatment, 20%
of patients receiving CaMg had neuropathy compared to 45% of patients
receiving chemotherapy alone. The percentage of patients who withdrew
from treatment due to any toxicity was 33% in patients receiving CaMg
and 51% in patients receiving chemotherapy alone. The percentage of
patients who withdrew due to neurotoxicity was only 4% in patients
receiving CaMg and 31% in patients receiving chemotherapy alone. The
percentage of patients who withdrew due to grade 3 chronic neurotoxicity
was 0% in patients receiving CaMg and 12% in patients receiving chemotherapy
alone. With regard to chronic neuropathy at the end of treatment, 65%
of patients receiving CaMg had no neuropathy and only 37% receiving
chemotherapy alone did not have neuropathy. The duration of neuropathy
equal or greater than 2 was longer in patients receiving chemotherapy
alone. For example, patients on the FOLFOX 4 chemotherapy regimen receiving
CaMg had neuropathy lasting two months, and patients receiving chemotherapy
alone for 12 months. Chronic grade 3 neuropathy at the end of treatment
was 8% in patients receiving CaMg and 20% in patients receiving chemotherapy
alone. Grade 3 neuropathy is defined by the National Cancer Institute
as “paresthesia
interfering with function, severe objective sensory loss” and in
the case specific to oxaliplatin as “paresthesia, dysesthesia
causing functional impairment.”
Other chemotherapy-induced toxicities were also mitigated. Diarrhea greater
or equal to grade 2 occurred in only 10% percent of chemotherapy cycles
for patients receiving CaMg, and 27% for patients receiving chemotherapy
alone. Asthenia greater or equal to grade 2 occurred in only 13% percent
of chemotherapy cycles for patients receiving CaMg and 41% for patients
receiving chemotherapy alone. Stable weight was 92% in patients receiving
CaMg and only 75% in patients receiving chemotherapy alone. (Gamelin,
Boisdron-Celle et al. 2004)
An encouraging case report emerged a few years later showing how a protocol
using calcium gluconate and magnesium sulfate helped a woman continue
chemotherapy. A 40-year-old woman had 4 out of 6 weeks of one cycle of
the FLOX chemotherapy regimen (500 mg per m2 5-fluorouracil weekly, 500
mg per m2 folinic acid and 85 mg per m2 oxaliplatin). During the first
infusion of oxaliplatin, she experienced severe nausea and vomiting as
well as a headache and loss of vision in her right eye, which resolved
in 24 hours. The administration of the second dose of oxaliplatin was
extended to three hours, however she developed severe chest pain, headache
and loss of vision, for which she received diphenhydramine and hydrocortisone
and recovered in the emergency room with intravenous support.
Then the patient was referred to Yale New Haven Hospital (Yale University
School of Medicine) where she received intravenous calcium gluconate
1 g and magnesium sulfate 1 g prior to and following the FOLFOX 6 chemotherapy
regimen. Prior to chemotherapy she also received famotidine, diphenhydramine,
ondansetron, and decadron. The patient did not develop any of the side
effects that she experienced during the prior treatments with oxaliplatin.
She successfully completed nine cycles of FOLFOX 6 using the same medications
mentioned previously. (Wrzesinski, McGurk et al. 2007)
GLUTATHIONE
A randomized, double-blind, placebo-controlled clinical trial was conducted
to assess glutathione in the prevention of neurotoxicity induced by oxaliplatin-based
chemotherapy. Fifty-two patients with advanced colorectal cancer were
enrolled: 26 patients received chemotherapy (oxaliplatin, 5-fluorouracil,
and leucovorin) with normal saline solution (as a placebo) and 26 patients
received the same chemotherapy with glutathione (1,500 mg per m2). Evaluations
of neurotoxicity were performed at baseline and after 4, 8, and 12 cycles
of treatment.
After the fourth chemotherapy cycle, 7 out of 26 patients in the GSH
group had neuropathy (grade 1-2) and 11 out of 26 patients in the placebo
group had neuropathy (grade 1-2). After the eighth cycle, 9 out of
21 evaluable patients in the GSH group had neuropathy (grade 1-2).
The nineteen evaluable patients in the placebo group didn’t fare
as well, with 10 patients having grade 1-2 neuropathy and 5 patients
having grade 3-4 neuropathy. After twelve cycles, 8 out of 10 evaluable
patients in the GSH group had grade 1-2 neuropathy and one patient
had grade 3 neuropathy. In the placebo group, 2 out of 8 evaluable
patients had grade 1-2 neuropathy and 6 patients had grade 3-4 neuropathy.
After eight cycles, 11 out of 19 patients in the placebo group and only
2 out of 21 patients in the GSH group had grade 2-4 neuropathy. After
12 cycles, 8 out of 8 patients in the placebo arm and only 3 out of 10
in the GSH arm had grade 2-4 neuropathy. Sural sensory nerve conduction
was reduced significantly in the placebo group but not in the GSH group.
The overall response rate to treatment was slightly higher in the GSH
group at 26.9% and was 23.1% in the placebo arm, thus showing no reduction
in the efficacy of chemotherapy treatment. This study provides evidence
that GSH is promising as a therapy for the prevention of oxaliplatin-induced
neuropathy, and that GSH does not interfere with the anti-tumor effect
of this chemotherapy regimen. (Cascinu, Catalano et al. 2002; Arnould,
Hennebelle et al. 2003)
N-ACETYL CYSTEINE
Fourteen stage III colon cancer patients were enrolled in a clinical
trial to assess whether oral N-acetyl cysteine could reduce neurotoxicity
induced by a chemotherapy regimen including oxaliplatin, 5-fluorouracil,
and low dose leucovorin. Five patients (group-A) received a combination
of chemotherapy and N-acetyl cysteine (1,200 mg). Nine patients (group-B)
received chemotherapy alone. Evaluations were made at the onset of treatment
and after 4, 8, and 12 treatment cycles. After four cycles of chemotherapy,
40% in group-A had grade 1 neuropathy compared to 77.8% in group-B. After
eight cycles of chemotherapy, 60% in group-A had grade 1 neuropathy and
none had a higher grade of neuropathy. In contrast, patients in group-B
began to develop higher grades of neuropathy, with 44.4% still at grade
1, but 55.6% now progressed to grade 2 neuropathy. After twelve cycles
of chemotherapy, 60% in group-A had grade 1 neuropathy and 20% had grade
2 neuropathy. In group-B, 11.1% had grade 1 neuropathy, 55.6% had grade
2 neuropathy, and 33.3% developed grade 3 neuropathy. Therefore patients
receiving N-acetyl cysteine developed significantly less neuropathy.
(Lin, Lee et al. 2006)
Tegafur
N-ACETYL CYSTEINE
N-acetyl cysteine did not significantly alter the activity of tegafur
in colon cancer cells. However, N-acetyl cysteine did reduce the effectiveness
of a very new drug that is a derivative of tegafur, called butyroyloxymethyl-tegafur
derivative 3. (Engel, Nudelman et al. 2008)
POLYSACCHARIDE-K (PSK)
Polysaccharide-K (PSK) is extracted from a mushroom called turkey tail.
Other names include Trametes versicolor and Coriolus versicolor (Latin),
yun zhi (Chinese), and kawaratake (Japanese). It is commonly used to
boost immune health and often used with cancer patients.
» PSK: Typical doses for cancer patients range between 2 to
6 g.
In an animal study, the chemotherapy combination of tegafur (Uracil)
(UFT) plus leucovorin (LV) was weakly effective with colon cancer. The
addition of PSK did not make the anti-tumor treatment any more or less
effective. The same was true for Lewis lung cancer. However, in Meth
A sarcoma, PSK did enhance this chemotherapy regimen. (Katoh and Ooshiro
2007)
Paclitaxel
COMBINATIONS TO AVOID: N-ACETYL CYSTEINE
In an animal study using mice with colon cancer, N-acetyl cysteine interfered
with the anti-tumor activity of paclitaxel when used in combination.
However N-acetyl cysteine did prevent toxicity to blood cells due to
paclitaxel. Because this study reports that N-acetyl cysteine can reduce
effectiveness of paclitaxel, we recommend not using this combination.
(Alexandre, Nicco et al. 2006)
Pemetrexed
FOLIC ACID AND VITAMIN B12
Vitamin B12, also known as cobalamins, can be found in various dietary
sources, including liver, meat, eggs, milk, and saltwater fish.
» Vitamin B12: Typical adult doses range from 1 to 3 micrograms
per day.
Folic acid, also known as vitamin B9, is found in dietary sources such
as dark leafy green vegetables, liver, egg yolk, various beans, and peas.
» Vitamin B9: Typical adult doses range from 300 micrograms to
no more than 900 micrograms per day.
In the earlier stages of developing pemetrexed as a treatment for cancer
(mostly used for malignant pleural mesothelioma and non-small cell lung
cancer, but having activity against colon cancer as well), life threatening
toxicities were encountered. It was soon discovered that supplementation
with folic acid and vitamin B12 could minimize these toxicities when
included in the treatment regimen. (Curtin and Hughes 2001; Scagliotti
and Novello 2003)
....................................................................................................................
REFERENCES AND SELECT STUDY ABSTRACTS
Adams, J. M. and S. Cory (2007). "Bcl-2-regulated apoptosis: mechanism and
therapeutic potential." Curr Opin Immunol 19(5): 488-96.
Apoptosis is essential
for tissue homeostasis, particularly in the hematopoietic compartment, where
its impairment can elicit neoplastic or autoimmune diseases. Whether stressed
cells live or die is largely determined by interplay between opposing members
of the Bcl-2 protein family. Bcl-2 and its closest homologs promote cell
survival, but two other factions promote apoptosis. The BH3-only proteins
sense and relay stress signals, but commitment to apoptosis requires Bax
or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly,
by engaging and neutralizing their pro-survival relatives, which otherwise
constrain Bax and Bak from permeabilizing mitochondria. The Bcl-2 family
may also regulate autophagy and mitochondrial fission/fusion. Its pro-survival
members are attractive therapeutic targets in cancer and perhaps autoimmunity
and viral infections.
Adeyemo, D., F. Imtiaz, et al. (2001). "Antioxidants
enhance the susceptibility of colon carcinoma cells to 5-fluorouracil by
augmenting the induction of the bax protein." Cancer Lett 164(1): 77-84.
5 Fluorouracil (5 FU), the most effective systemic chemotherapeutic agent
in the management of advanced colorectal carcinoma acts by inducing apoptosis.
Response rates, approximately 20% is improved by folinic acid. This study
investigates similar modulation of 5 FU-induced apoptosis by oxidant quenching.
A five-fold reduction of intracellular oxidant levels by antioxidants N-acetylcysteine
and vitamin E did not induce apoptosis, it however augmented pro-apoptotic
bax protein expression, and apoptotic response to a non-toxic dose of 5 FU
in the colorectal cancer cell lines colo 201 and colo 205. This suggests
that reduction of intracellular levels of reactive oxygen species enhance
susceptibility to 5 FU (apoptotic stimuli) by augmentation of bax expression.
Alexandre, J., C. Nicco, et al. (2006). "Improvement of the therapeutic index
of anticancer drugs by the superoxide dismutase mimic mangafodipir." J Natl
Cancer Inst 98(4): 236-44.
BACKGROUND: Anticancer drugs act by increasing
intracellular hydrogen peroxide levels. Mangafodipir, a superoxide dismutase
(SOD) mimic with catalase and glutathione reductase activities, protects
normal cells from apoptosis induced by H2O2. We investigated its and other
oxidative stress modulators' effects on anticancer drug activity in vitro
and in vivo. METHODS: Cell lysis and intracellular reactive oxygen species
levels were assessed in vitro in human leukocytes from healthy subjects
and in murine CT26 colon cancer cells. Cells were exposed to the chemotherapeutic
agents paclitaxel, oxaliplatin, or 5-fluorouracil, either in the presence
or absence of mangafodipir and other oxidative stress modulators. Cell
viability was evaluated by the methylthiazoletetrazolium assay. The effects
of mangafodipir and other oxidative stress modulators on peripheral blood
counts and on tumor growth were studied in BALB/c mice that were implanted
with CT26 tumors and treated with 20 mg/kg paclitaxel. Survival of BALB/c
mice infected with Staphylococcus aureus was also examined by treatment
group. Statistical tests were two-sided. RESULTS: In vitro lysis of leukocytes
exposed to paclitaxel, oxaliplatin, or 5-fluorouracil in combination with
mangafodipir was decreased by 46% (95% confidence interval [CI] = 44% to
48%), 30.5% (95% CI = 29% to 32%), and 15% (95% CI = 10% to 20%), compared
with lysis of cells treated with anticancer agent alone. Mangafodipir also
statistically significantly enhanced in vitro anticancer drug cytotoxicity
toward CT26 cancer cells. In vivo, mangafodipir protected mice against
paclitaxel-induced leukopenia. Moreover, the survival rate of mice infected
with S. aureus and treated with paclitaxel was higher when mangafodipir
was also administered (survival: 3 of 17 versus 14 of 17, P < .001). In
addition, mangafodipir amplified the inhibitory effect of paclitaxel on
CT26 tumor growth in mice. CONCLUSIONS: Mangafodipir decreased hematotoxicity
and enhanced cytotoxicity of anticancer agents.
Arnould, S., I. Hennebelle,
et al. (2003). "Cellular determinants of oxaliplatin sensitivity in colon
cancer cell lines." Eur J Cancer 39(1): 112-9.
Oxaliplatin (L-OHP) is a new
platinum analogue that has shown antitumour activity against colon cancer
both in vitro and in vivo and is now used in the chemotherapeutic treatment
of metastatic colon and rectal cancer. L-OHP like cisplatin (CDDP), is detoxified
by glutathione (GSH)-related enzymes and forms platinum (Pt)-DNA adducts
lesions that are repaired by the nucleotide excision repair system (NER).
We investigated the cytotoxicity and the pharmacology of L-OHP and CDDP on
a panel of six colon cell lines in vitro. We showed that GSH and glutathione
S-transferase (GST) activity were not correlated to oxaliplatin cytotoxicity.
Pt-DNA adducts formation and repair were correlated with CDDP, but not with
L-OHP cytotoxicity. The determination of ERCC1 and XPA expression, two enzymes
of the NER pathway, by reverse transcriptase-polymerase chain reaction (RT-PCR),
demonstrated that ERCC1 expression was predictive of L-OHP sensitivity (r(2)=0.67,
P=0.02) and XPA level after oxaliplatin exposure was also correlated to L-OHP
IC(50) (r(2)=0.5; P=0.04). The knowledge of such correlations could help
predict the sensitivity of patients with colon cancer to L-OHP.
Bakhle, Y.
S. (2001). "COX-2 and cancer: a new approach to an old problem." Br J Pharmacol
134(6): 1137-50.
Barni, S., P. Lissoni, et al. (1995). "A randomized study
of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care
alone in metastatic colorectal cancer patients progressing under 5-fluorouracil
and folates." Oncology 52(3): 243-5.
Chemotherapy with 5-fluorouracil (5-FU)
and folates represents the first-line standard therapy for metastatic colorectal
cancer, whereas at present there is no conventional second-time treatment.
Because of its importance in generating an effective anticancer immune
response, interleukin-2 (IL-2) could constitute a new promising therapy
of advanced colon cancer. Generally, IL-2 may determine tumor regressions
in colon cancer only when it is given at high toxic doses. Our preliminary
studies have shown that the pineal hormone melatonin may amplify IL-2 activity,
which becomes active also at low doses in several tumor histotypes. On
the basis, we have performed a clinical trial to evaluate the impact of
low-dose IL-2 plus melatonin on the survival time in metastatic colon cancer,
which progressed in response to 5-FU plus folates. The study included 50
metastatic colorectal cancer patients, who did not respond or progressed
after initial response to first-line chemotherapy with 5-FU and folates.
Patients were randomized to receive supportive care alone or low-dose subcutaneous
IL-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40
mg/day orally). No spontaneous tumor regression occurred in patients receiving
supportive care alone. A partial response was achieved in 3/25 patients
treated with immunotherapy. Percent survival at 1 year was significantly
higher in patients treated with immunotherapy than in those treated with
supportive care alone (9/25 vs. 3/25, p < 0.05).
This study suggests that low-dose subcutaneous IL-2 plus melatonin may
be effective as a second-line therapy to induce tumor regression and to
prolong percent survival at 1 year in metastatic colorectal cancer patients
progressing under 5-FU and folates.
Barni, S., P. Lissoni, et al. (1992). "Neuroimmunotherapy
with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin
as a second-line treatment in metastatic colorectal carcinoma." Tumori 78(6):
383-7.
On the basis of our previous preliminary data which showed that the
pineal hormone melatonin (MLT) may potentiate IL-2 activity and reduce the
dose of IL-2 required to determine an effective host antitumor response,
we performed a clinical study with low-dose IL-2 given once/day subcutaneously
(3 million IU/day for 6 days/week for 4 weeks) in association with MLT (50
mg/day orally at 8.00 p.m. every day) as a second-line therapy in metastatic
colorectal cancer patients pretreated with 5-fluorouracil. Evaluable patients
were 13/14, and most of them showed disseminated liver metastases. No objective
tumor regression was seen. A stabilization of disease was achieved in 4/13
patients (median duration 5+ months), and the other 9 patients progressed.
Mean number of lymphocytes and eosinophils significantly increased during
the treatment. Moreover, the mean increase in lymphocyte number was significantly
higher in patients with stable disease than in those with progressive disease,
whereas there was no difference as regards eosinophils. Serum levels of neopterin
and tumor necrosis factor (TNF) significantly increased during therapy, and
TNF increase was correlated to the side effects rather than to the control
of cancer development. This study shows that neuroimmunotherapy with low-dose
interleukin-2 and MLT, even though capable of determining an evident expansion
of immune cells involved in host antitumor response, does not seem to be
effective in terms of tumor regression in metastatic colon cancer patients
pretreated with 5-fluorouracil.
Calviello, G., F. Di Nicuolo, et al. (2005). "Docosahexaenoic
acid enhances the susceptibility of human colorectal cancer cells to 5-fluorouracil." Cancer
Chemother Pharmacol 55(1): 12-20.
PURPOSE: Powerful growth-inhibitory action
has been shown for n-3 polyunsaturated fatty acids against colon cancer
cells. We have previously described their ability to inhibit proliferation
of colon epithelial cells in patients at high risk of colon cancer. In
the work reported here we investigated the ability of docosahexaenoic acid
(DHA) to potentiate the antineoplastic activity of 5-fluorouracil (5-FU)
in p53-wildtype (LS-174 and Colo 320) and p53-mutant (HT-29 and Colo 205)
human colon cancer cells. METHODS: When in combination with DHA, 5-FU was
used at concentrations ranging from 0.1 to 1.0 microM, much lower than
those currently found in plasma patients after infusion of this drug. Similarly,
the DHA concentrations (< or =10
microM) used in combination with 5-FU were lower than those widely used
in vitro and known to cause peroxidative effects in vivo. RESULTS: Whereas
the cells showed different sensitivity to the growth-inhibitory action
of 5-FU, DHA reduced cell growth independently of p53 cellular status.
DHA synergized with 5-FU in reducing colon cancer cell growth. The potentiating
effect of DHA was attributable to the enhancement of the proapoptotic effect
of 5-FU. DHA markedly increased the inhibitory effect of 5-FU on the expression
of the antiapoptotic proteins BCL-2 and BCL-XL, and induced overexpression
of c-MYC which has recently been shown to drive apoptosis and, when overexpressed,
to sensitize cancer cells to the action of proapoptotic agents, including
5-FU. CONCLUSION: Our results indicate that DHA strongly increases the
antineoplastic effects of low concentrations of 5-FU. Overall, the results
suggest that combinations of low doses of the two compounds could represent
a chemotherapeutic approach with low toxicity.
Cao, S., F. A. Durrani, et al. (2004). "Selective
modulation of the therapeutic efficacy of anticancer drugs by selenium containing
compounds against human tumor xenografts." Clin Cancer Res 10(7): 2561-9.
PURPOSE: Studies were carried out in athymic nude mice bearing human squamous
cell carcinoma of the head and neck (FaDu and A253) and colon carcinoma (HCT-8
and HT-29) xenografts to evaluate the potential role of selenium-containing
compounds as selective modulators of the toxicity and antitumor activity
of selected anticancer drugs with particular emphasis on irinotecan, a topoisomerase
I poison. EXPERIMENTAL DESIGN: Antitumor activity and toxicity were evaluated
using nontoxic doses (0.2 mg/mouse/day) and schedule (14-28 days) of the
selenium-containing compounds, 5-methylselenocysteine and seleno-L-methionine,
administered orally to nude mice daily for 7 days before i.v. administration
of anticancer drugs, with continued selenium treatment for 7-21 days, depending
on anticancer drugs under evaluation. Several doses of anticancer drugs were
used, including the maximum tolerated dose (MTD) and toxic doses. Although
many chemotherapeutic agents were evaluated for toxicity protection by selenium,
data on antitumor activity were primarily obtained using the MTD, 2 x MTD,
and 3 x MTD of weekly x4 schedule of irinotecan. RESULTS: Selenium was highly
protective against toxicity induced by a variety of chemotherapeutic agents.
Furthermore, selenium increased significantly the cure rate of xenografts
bearing human tumors that are sensitive (HCT-8 and FaDu) and resistant (HT-29
and A253) to irinotecan. The high cure rate (100%) was achieved in nude mice
bearing HCT-8 and FaDu xenografts treated with the MTD of irinotecan (100
mg/kg/week x 4) when combined with selenium. Administration of higher doses
of irinotecan (200 and 300 mg/kg/week x 4) was required to achieve high cure
rate for HT-29 and A253 xenografts. Administration of these higher doses
was possible due to selective protection of normal tissues by selenium. Thus,
the use of selenium as selective modulator of the therapeutic efficacy of
anticancer drugs is new and novel. CONCLUSIONS: We demonstrated that selenium
is a highly effective modulator of the therapeutic efficacy and selectivity
of anticancer drugs in nude mice bearing human tumor xenografts of colon
carcinoma and squamous cell carcinoma of the head and neck. The observed
in vivo synergic interaction is highly dependent on the schedule of selenium.
Cascinu, S., V. Catalano, et al. (2002). "Neuroprotective effect of reduced
glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer:
a randomized, double-blind, placebo-controlled trial." J Clin Oncol 20(16):
3478-83.
PURPOSE: We performed a randomized, double-blind, placebo-controlled
trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced
neurotoxicity. PATIENTS AND METHODS: Fifty-two patients treated with a bimonthly
oxaliplatin-based regimen were randomized to receive GSH (1,500 mg/m(2) over
a 15-minute infusion period before oxaliplatin) or normal saline solution.
Clinical neurologic evaluation and electrophysiologic investigations were
performed at baseline and after four (oxaliplatin dose, 400 mg/m(2)), eight
(oxaliplatin dose, 800 mg/m(2)), and 12 (oxaliplatin dose, 1,200 mg/m(2))
cycles of treatment. RESULTS: At the fourth cycle, seven patients showed
clinically evident neuropathy in the GSH arm, whereas 11 patients in the
placebo arm did. After the eighth cycle, nine of 21 assessable patients in
the GSH arm suffered from neurotoxicity compared with 15 of 19 in the placebo
arm. With regard to grade 2 to 4 National Cancer Institute common toxicity
criteria, 11 patients experienced neuropathy in the placebo arm compared
with only two patients in the GSH arm (P =.003). After 12 cycles, grade 2
to 4 neurotoxicity was observed in three patients in the GSH arm and in eight
patients in the placebo arm (P =.004). The neurophysiologic investigations
(sural sensory nerve conduction) showed a statistically significant reduction
of the values in the placebo arm but not in the GSH arm. The response rate
was 26.9% in the GSH arm and 23.1% in the placebo arm, showing no reduction
in activity of oxaliplatin. CONCLUSION: This study provides evidence that
GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy,
and that it does not reduce the clinical activity of oxaliplatin.
Cerea,
G., M. Vaghi, et al. (2003). "Biomodulation of cancer chemotherapy for metastatic
colorectal cancer: a randomized study of weekly low-dose irinotecan alone
versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic
colorectal cancer patients progressing on 5-fluorouracil-containing combinations." Anticancer
Res 23(2C): 1951-4.
Recent advances in immunobiological knowledge have suggested
the possibility of enhancing the therapeutic activity of various chemotherapeutic
agents by a concomitant administration of anti-oxidant drugs and/or immunomodulating
neurohormones. In particular, the pineal neurohormone melatonin (MLT),
which is able to exert both antioxidant and immunomodulating effects, has
been proven to enhance the efficacy of various chemotherapeutic drugs,
namely cisplatin, anthracyclines and 5-fluorouracil, whereas at present
there are no data about its possible influence on cytotoxic drugs effective
in the treatment of colon cancer other than 5-fluorouracil, such as irinotecan
(CPT-11). The present study was performed to evaluate the influence of
a concomitant administration of MLT on CPT-11 therapeutic activity in metastatic
colorectal cancer. The study included 30 metastatic colorectal cancer patients
progressing after at least one previous chemotherapeutic line containing
5-fluorouracil, who were randomized to be treated with CPT-11 alone or
CPT-11 plus MLT. According to a weekly low-dose schedule, CPT-11 was given
i.v. at 125 mg/m2/week for 9 consecutive weeks. MLT was administered orally
at 20 mg/day during the dark period of the day. No complete response was
observed. A partial response (PR) was achieved in 2 out of 16 patients
treated with CPT-11 alone and in 5 out of 14 patients concomitantly treated
with MLT. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients
treated with CPT-11 alone and in 7 out of 14 patients treated with CPT-11
plus MLT. Therefore, the percent of disease-control achieved in patients
concomitantly treated with MLT was significantly higher than that observed
in those treated with chemotherapy alone (12 out of 14 vs 7 out of 16,
p < 0.05). The only important toxicity
was diarrhoea grade 3-4, which occurred in 6 out of 16 patients treated
with CPT-11 alone and in 4 out of 14 patients treated with CPT-11 plus
MLT, which required a 50% dose reduction. However, taken together, patients
treated with CPT-11 at 50% of the planned dose showed a percent of disease
control comparable to that achieved in patients who had no dose reduction
(6 out of 10 vs 13 out of 20). This preliminary study shows that the efficacy
of weekly low-dose CPT-11 in pretreated metastatic colorectal cancer patients
may be enhanced by a concomitant daily administration of the pineal hormone
MLT, according to the results previously reported for other chemotherapeutic
agents. Moreover, since the dose reduction of CPT-11 does not influence
its efficacy, the dose of CPT-11 for successive studies might be not greater
than 70 mg/m2.
Chauhan, D. P. (2002). "Chemotherapeutic potential of curcumin
for colorectal cancer." Curr Pharm Des 8(19): 1695-706.
Colorectal cancer
is one of the leading causes of cancer deaths in the Western world. More
than 56,000 newly diagnosed colorectal cancer patients die each year in the
United States. Available therapies are either not effective or have unwanted
side effects. Epidemiological data suggest that dietary manipulations play
an important role in the prevention of many human cancers. Curcumin the yellow
pigment in turmeric has been widely used for centuries in the Asian countries
without any toxic effects. Epidemiological data also suggest that curcumin
may be responsible for the lower rate of colorectal cancer in these countries.
Curcumin is a naturally occurring powerful anti-inflammatory medicine. The
anticancer properties of curcumin have been shown in cultured cells and animal
studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor
of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis
by inhibiting the cytochrome P-450 enzyme activity and increasing the levels
of glutathione-S-transferase. Curcumin inhibits the promotion/progression
stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed
in part to the arrest of cancer cells in S, G2/M cell cycle phase and induction
of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective
colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic
agent for the treatment of tumors exhibiting DNA mismatch repair deficient
and microsatellite instable phenotype. Curcumin should be considered as a
safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers
arise in the setting of chromosomal instability as well as microsatellite
instability.
Chen, M. F., L. T. Chen, et al. (1995). "Effect of 5-fluorouracil
on methotrexate transport and cytotoxicity in HT29 colon adenocarcinoma cells." Cancer
Lett 88(2): 133-40.
Exposure of the human colon adenocarcinoma HT29 cells
to different concentrations of 5-fluorouracil (5FU) for 24 h resulted in
a dose-dependent increase in the cellular glutathione (GSH) level which remained
elevated up to 72 h following 5FU treatment. Pretreatment of HT29 cells with
5FU was found to enhance the uptake of methotrexate (MTX) as compared to
control cells. Administration of MTX 24 h after 5FU was found to be synergistic,
whereas administration of MTX 24 h before 5FU or together with 5FU was not
found to be synergistic. The results of this study suggest that the increase
in cellular GSH level as a result of 5FU pretreatment may play a role in
the enhancement of MTX uptake and the cytotoxicity of both drugs in HT29
cells.
Chen, M. F., L. T. Chen, et al. (1995). "5-Fluorouracil cytotoxicity
in human colon HT-29 cells with moderately increased or decreased cellular
glutathione level." Anticancer Res 15(1): 163-7.
Little is known whether
diet or certain components in the diet can modulate the efficacy of 5-fluorouracil
(5FU) in patients with colon carcinoma. Glutathione (GSH), an important antioxidant
and anticarcinogen, is present in many foods in varying amounts. This study
examined whether a moderately increased or decreased cellular GSH level had
any effect on the growth of human colon adenocarcinoma cells HT-29 and on
the cytotoxic activity of 5FU in these cells. GSH and buthionine sulfoximine
were used to enhance or reduce the GSH level respectively in these cells.
A 34% increase in cellular GSH level had no effect on the growth of HT-29
cells, nor on the cytotoxic activity of 5FU as determined by the MTT colorimetric
assay and cell counts. A 50% reduction in the cellular GSH level was found
to enhance 5FU cytotoxicity by 20% to 31% as determined by the MTT colorimetric
assay, depending on the 5FU concentration. This study shows that a moderate
change in the GSH level in HT-29 cells had little or no effect on the cells'
growth, but a decrease in cellular GSH level slightly enhanced the cytotoxic
activity of 5FU in these cells.
Chinery, R., J. A. Brockman, et al. (1997). "Antioxidants
enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer:
a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta." Nat Med 3(11):
1233-41.
Colorectal cancer (CRC) is the second leading cause of cancer deaths
in the United States. Five-fluorouracil (5FU) remains the single most effective
treatment for advanced disease, despite a response rate of only 20%. Herein,
we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce
apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1,
a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta
(a member of the CCAAT/enhancer binding protein family of transcription factors),
independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition
by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU).
Thus, chemotherapeutic agents administered in the presence of antioxidants
may provide a novel therapy for colorectal cancer.
Choo, M. K., H. Sakurai,
et al. (2008). "A ginseng saponin metabolite suppresses tumor necrosis factor-alpha-promoted
metastasis by suppressing nuclear factor-kappaB signaling in murine colon
cancer cells." Oncol Rep 19(3): 595-600.
SC-514, an inhibitor of IkappaB
kinase beta (IKKbeta), blocked the TNF-alpha-induced activation of nuclear
factor-kappaB (NF-kappaB) as well as the TNF-alpha-promoted metastasis of
murine colon adenocarcinoma cells. We investigated the effect of 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol
(M1), a main intestinal bacterial metabolite of ginseng, on the NF-kappaB-dependent
metastasis. M1 was effective in suppressing the TNF-alpha-induced activation
of NF-kappaB, expression of matrix metalloprotease-9 (MMP-9), migration and
invasion. The TNF-alpha-evoked increase in lung and liver metastasis of colon
carcinoma was also abrogated by treatment with M1 in vitro. These results
suggest that ginseng has potential to suppress inflammation-related metastasis
by downregulating the NF-kappaB signaling pathway.
Conklin, K. A. (2000). "Dietary
antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness
and development of side effects." Nutr Cancer 37(1): 1-18.
Curtin, N. J.
and A. N. Hughes (2001). "Pemetrexed disodium, a novel antifolate with multiple
targets." Lancet Oncol 2(5): 298-306.
Pemetrexed disodium is a potent new
antifolate which inhibits many folate-dependent reactions that are essential
for cell proliferation. Its primary target is thymidylate synthase but it
also inhibits folate-dependent enzymes involved in purine synthesis. Cells
that are resistant to antifolates are generally less resistant to pemetrexed,
irrespective of the mechanism of resistance. Pemetrexed has shown good activity
in preclinical models with human tumour cells and xenografts. In the majority
of clinical trials of pemetrexed, the dose-limiting toxic effect is neutropenia;
other side-effects are mostly gastrointestinal. Preclinical studies indicate
that the toxic effects of pemetrexed can be reduced by dietary folate, resulting
in an improved therapeutic index. Low folate status is also associated with
higher levels of toxicity in patients. As a single agent pemetrexed has shown
good activity against non-small-cell lung cancer, squamous-cell carcinoma
of head and neck, colon cancer, and breast cancer, and it appears to be particularly
active in combination with cisplatin against non-small-cell lung cancer and
mesothelioma. Phase II and III studies are underway.
Daniele, B., F. Perrone,
et al. (2001). "Oral glutamine in the prevention of fluorouracil induced
intestinal toxicity: a double blind, placebo controlled, randomised trial." Gut
48(1): 28-33.
BACKGROUND: 5-Fluorouracil (FU) in association with folinic
acid (FA) is the most frequently used chemotherapeutic agent in colorectal
cancer but it often causes diarrhoea. Animal and human studies suggest that
glutamine stimulates intestinal mucosal growth. AIM: To determine if oral
glutamine prevents changes in intestinal absorption (IA) and permeability
(IP) induced by FU/FA. METHODS: Seventy chemotherapy naive patients with
colorectal cancer were randomly assigned to oral glutamine (18 g/day) or
placebo before the first cycle of FU (450 mg/m(2)) and FA (100 mg/m(2)) administered
intravenously for five days. Treatment was continued for 15 days, starting
five days before the beginning of chemotherapy. IA (D-xylose urinary excretion)
and IP (cellobiose-mannitol test) were assessed at baseline and four and
five days after the end of the first cycle of chemotherapy, respectively.
Patients kept a daily record of diarrhoea, scored using the classification
system of the National Cancer Institute (Bethesda, Maryland, USA). Duration
of diarrhoea was recorded and the area under the curve (AUC) was calculated
for each patient. RESULTS: Baseline patient characteristics and basal values
of IP and IA tests were similar in the two arms. After one cycle of chemotherapy,
the reduction in IA (D-xylose absorption) was more marked in the placebo
arm (7.1% v 3. 8%; p=0.02); reduction of IP to mannitol was higher in the
placebo arm (9.2% v 4.5%; p=0.02); and urinary recovery of cellobiose was
not different between the study arms (p=0.60). Accordingly, the cellobiose-mannitol
ratio increased more in the placebo arm (0.037 v 0.012; p=0.04). Average
AUC of diarrhoea (1.9 v 4.5; p=0.09) and average number of loperamide tablets
taken (0.4 v 2.6; p=0.002) were reduced in the glutamine arm. CONCLUSIONS:
Glutamine reduces changes in IA and IP induced by FU and may have a protective
effect on FU induced diarrhoea.
Doyle, L. A., D. D. Ross, et al. (1995). "An
etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated
protein." Br J Cancer 72(3): 535-42.
Du, B., L. Jiang, et al. (2006). "Synergistic
inhibitory effects of curcumin and 5-fluorouracil on the growth of the human
colon cancer cell line HT-29." Chemotherapy 52(1): 23-8.
The synergistic
effect of combination treatment with COX-2 inhibitors and chemotherapy may
be another promising therapy regimen in the future treatment of colorectal
cancer. Curcumin, a major yellow pigment in turmeric which is used widely
all over the world, inhibits the growth of human colon cancer cell line HT-29
significantly and specifically inhibits the expression of COX-2 protein.
However, the worldwide exposure of populations to curcumin raised the question
of whether this agent would enhance or inhibit the effects of chemotherapy.
In this report, we evaluated the growth-inhibitory effect of curcumin and
a traditional chemotherapy agent, 5-FU, against the proliferation of a human
colon cancer cell line (HT-29). The combination effect was quantitatively
determined using the method of median-effect principle and the combination
index. The inhibition of COX-2 expression after treatment with the curcumin-5-FU
combination was also evaluated by Western blot analysis. The IC(50) value
in the HT-29 cells for curcumin was 15.9 +/- 1.96 microM and for 5-FU it
was 17.3 +/- 1.85 microM. When curcumin and 5-FU were used concurrently,
synergistic inhibition of growth was quantitatively demonstrated. The level
of COX-2 protein expression was reduced almost 6-fold after the combination
treatment. Our results demonstrate synergism between curcumin and 5-FU at
higher doses against the human colon cancer cell line HT-29. This synergism
was associated with the decreased expression of COX-2 protein.
Engel, D.,
A. Nudelman, et al. (2008). "Novel Prodrugs of Tegafur that Display Improved
Anticancer Activity and Antiangiogenic Properties." J Med Chem 51(2): 314-23.
New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation
or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione
(tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur
derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine,
suggesting that the increased activity of the prodrug is in part mediated
by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel
assay was found to be a more potent antiangiogenic agent than tegafur. In
vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast
carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors
in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur
display selectivity toward cancer cells, antiangiogenic activity, and anticancer
activities in vitro and in vivo, superior to those of tegafur. 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4(1
H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely
used for treatment of gastrointestinal malignancies with modest efficacy.
The aim of this study was to develop and characterize new and more potent
prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation
of tegafur. Comparison between the effect of tegafur and the new prodrugs
on the viability of a variety of cancer cell lines showed that the IC 50
and IC 90 values of the novel prodrugs were 5-10-fold lower than those of
tegafur. While significant differences between the IC 50 values of tegafur
were observed between the sensitive HT-29 and the resistant LS-1034 colon
cancer cell lines, the prodrugs affected them to a similar degree, suggesting
that they overcame drug resistance. The increased potency of the prodrugs
could be attributed to the antiproliferative contribution imparted by formaldehyde
and butyric acid, released upon metabolic degradation. The anticancer activity
of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was
attenuated by the antioxidant N-acetylcysteine, suggesting that the increased
activity of the prodrug is in part mediated by an increase of reactive oxygen
species. Compound 3 in an in vitro matrigel assay was found to be a more
potent antiangiogenic agent than tegafur. In vivo 3 was significantly more
potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and
growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary,
the multifunctional prodrugs of tegafur display selectivity toward cancer
cells, antiangiogenic activity and anticancer activities in vitro and in
vivo, superior to those of tegafur.
Fernandez-Luna, J. L. (2007). "Apoptosis
regulators as targets for cancer therapy." Clin Transl Oncol 9(9): 555-62.
Apoptosis serves to remove excess or damaged cells and its dysregulation
may lead to a number of pathological disorders including cancer. Studies
during the last 20 years have unravelled much of the molecular mechanisms
that control apoptosis. Whether a cell dies in response to diverse apoptotic
stimuli, including DNA-damaging agents, is determined largely by interactions
between proteins of the Bcl-2 family. A death signal is transmitted through
the BH3-only proteins to Bax and Bak which in turn permeabilise the outer
mitochondrial membrane allowing the release of apoptogenic factors, which
triggers activation of cell-deathpromoting caspases. These proteolytic enzymes
are tightly controlled by members of the inhibitor of apoptosis (IAP) family.
Activation of the caspase cascade via cell death receptors also represents
a key apoptotic pathway in both normal and tumour cells. Basic knowledge
of these apoptosis regulators provides the basis for novel therapeutic strategies
aimed at promoting tumour cell death or enhancing susceptibility to apoptotic
inducers. This review focuses on these strategies.
Fogt, F., A. Wellmann,
et al. (2001). "Glut-1 expression in dysplastic and regenerative lesions
of the colon." Int J Mol Med 7(6): 615-9.
Monosaccaride transporter proteins
are responsible for transmembrane transport of monosaccarides into cells.
Glucose transporter protein 1 (Glut-1) is most prevalent in the cell membranes
of erythrocytes and facilitates transport of glucose in tissues with barrier
functions, i.e. blood brain barrier. Expression of Glut-1 in malignant tumors
is increased due to increased metabolic need of the proliferating cell populations.
In colorectal adenomas and carcinomas, membranous expression of Glut-1 has
been associated with higher grade of tumors and decreased survival time.
We studied the expression of Glut-1 in dysplastic proliferations of the colon
which included sporadic adenomas and dysplasia associated lesions (DALM)
in patients with ulcerative colitis and reactive/regenerative proliferations
of the colon, including non-dysplastic chronic colitis, acute colitis and
ischemia. Two patterns of Glut-1 expression were detected. Most adenomas
and DALMs showed at least focal membranous expression of Glut-1. In addition
a second staining pattern was recognized which consisted of prominent supranuclear
dots. This pattern of staining was not only seen in adenomas and DALM but
also in non-dysplastic areas immediately surrounding sporadic adenomas, in
regenerative chronic colitis and in areas surrounding acute inflammation.
Areas away from dysplasia did not show any positive staining for Glut-1.
We conclude that two distinct patterns of Glut-1 expression may be found
in colonic epithelial proliferation: membranous staining, associated with
dysplasia, and, heretofore not described, supranuclear staining which may
be related to Glut-1 expression secondary to expression of specific growth
factors and not necessarily related to dysplasia.
Gamelin, L., M. Boisdron-Celle,
et al. (2004). "Prevention of oxaliplatin-related neurotoxicity by calcium
and magnesium infusions: a retrospective study of 161 patients receiving
oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal
cancer." Clin Cancer Res 10(12 Pt 1): 4055-61.
PURPOSE: Oxaliplatin is active
in colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity.
It may come from an effect on neuronal voltage-gated Na channels, via the
liberation one its metabolite, oxalate. We decided to use Ca and Mg as oxalate
chelators. EXPERIMENTAL DESIGN: A retrospective cohort of 161 patients treated
with oxaliplatin + 5-fluorouracil and leucovorin for advanced colorectal
cancer, with three regimens of oxaliplatin (85 mg/m(2)/2w, 100/2w, 130/3w)
was identified. Ninety-six patients received infusions of Ca gluconate and
Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not.
RESULTS: Only 4% of patients withdrew for neurotoxicity in the Ca/Mg group
versus 31% in the control group (P = 0.000003). The tumor response rate was
similar in both groups. The percentage of patients with grade 3 distal paresthesia
was lower in Ca/Mg group (7 versus 26%, P = 0.001). Acute symptoms such as
distal and lingual paresthesia were much less frequent and severe (P = 10(-7)),
and pseudolaryngospasm was never reported in Ca/Mg group. At the end of the
treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P =
0.003). Patients with grade 2 and 3 at the end of the treatment in the 85
mg/m(2) oxaliplatin group recovered significantly more rapidly from neuropathy
than patients without Ca/Mg. CONCLUSIONS: Ca/Mg infusions seem to reduce
incidence and intensity of acute oxaliplatin-induced symptoms and might delay
cumulative neuropathy, especially in 85 mg/m(2) oxaliplatin dosage.
Goto,
S., K. Kamada, et al. (2002). "Significance of nuclear glutathione S-transferase
pi in resistance to anti-cancer drugs." Jpn J Cancer Res 93(9): 1047-56.
Recent study has shown that nuclear glutathione S-transferase (GST) pi accumulates
in cancer cells resistant to doxorubicin hydrochloride (DOX) and may function
to prevent nuclear DNA damage caused by DOX (Goto et al., FASEB J., 15, 2702
- 2714 (2001)). It is not clear if the amount of nuclear GSTpi increases
in response to other anti-cancer drugs and if so, what is the physiological
significance of the nuclear transfer of GSTpi in the acquisition of drug-resistance
in cancer cells. In the present study, we employed three cancer cell lines,
HCT8 human colonic cancer cells, A549 human lung adenocarcinoma cells, and
T98G human glioblastoma cells. We estimated the nuclear transfer of GSTpi
induced by the anti-cancer drugs cisplatin (CDDP), irinotecan hydrochloride
(CPT-11), etoposide (VP-16) and 5-fluorouracil (5-FU). It was found that:
(1) Nuclear GSTpi accumulated in these cancer cells in response to CDDP,
DOX, CPT-11, VP-16 and 5-FU. (2) An inhibitor of the nuclear transport of
GSTpi, edible mushroom lectin (Agaricus bisporus lectin, ABL), increased
the sensitivity of the cancer cells to DOX and CDDP, and partially to CPT-11.
Treatment with ABL had no apparent effect on the cytotoxicity of VP-16 and
5-FU. These results suggest that inhibitors of the nuclear transfer of GSTpi
have practical value in producing an increase of sensitivity to DOX, CDDP
and CPT-11.
Grubben, M. J., F. M. Nagengast, et al. (2001). "The glutathione
biotransformation system and colorectal cancer risk in humans." Scand J Gastroenterol
Suppl(234): 68-76.
Evidence for a protective role of the glutathione biotransformation
system in carcinogenesis is growing. However, most data on this system in
relation to colorectal cancer originate from animal studies. Here we review
the human data. In humans, a significant association was found between glutathione
S-transferase (GST) activity in the mucosa along the gastrointestinal tract
and the corresponding tumour incidence. Low activity was correlated with
high tumour incidence and vice versa. Also, in normal colonic mucosa, GST
activity is lower in patients at risk of colon cancer than in healthy controls
and therefore interventions which increase the glutathione detoxification
capacity may reduce cancer incidence. Consumption of vegetables and fruit
is associated with a lower risk of colorectal cancer. Human intervention
studies showed that (components from) vegetables induced colonic glutathione
detoxification capacity. Such an effect could contribute to a lower colon
cancer risk, but further data are needed. The human GSTs consist of four
main classes--alpha (A), mu (M), pi (P) and theta (T)--each of which is divided
into one or more isoforms. Functional polymorphisms are known for the GST
genes M1, P1 and T1 and they all lead to less active enzymes compared to
the wild-type gene products. However, studies that compared these GST polymorphisms
in relation to colon cancer risk were not conclusive with respect to an increased
or decreased risk of a particular genotype. Diet or medication can also influence
the expression levels of specific isoenzymes and the effect of such interventions
on cancer risk deserves more attention.
Hatcher, H., R. Planalp, et al. (2008). "Curcumin:
From ancient medicine to current clinical trials." Cell Mol Life Sci.
Curcumin
is the active ingredient in the traditional herbal remedy and dietary spice
turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial
properties, including anti-inflammatory, antioxidant, chemopreventive and
chemotherapeutic activity. The pleiotropic activities of curcumin derive
from its complex chemistry as well as its ability to influence multiple signaling
pathways, including survival pathways such as those regulated by NF-kappaB,
Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic
and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen
donor, and exhibits both pro- and antioxidant activity. It also binds metals,
particularly iron and copper, and can function as an iron chelator. Curcumin
is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits
great promise as a therapeutic agent, and is currently in human clinical
trials for a variety of conditions, including multiple myeloma, pancreatic
cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's
disease.
Hidvegi, M., E. Raso, et al. (1999). "MSC, a new benzoquinone-containing
natural product with antimetastatic effect." Cancer Biother Radiopharm 14(4):
277-89.
An orally applicable fermentation product of wheat germ containing
0.04% substituted benzoquinone (MSC) has been invented by Hungarian chemists
under the trade name of AVEMAR. Oral administration (3 g/kg body weight)
of MSC enhances blastic transformation of splenic lymphocytes in mice. The
same treatment shortens the survival time of skin grafts in a co-isogenic
mouse skin transplantation model, pointing to the immune-reconstructive effect
of MSC. A highly significant antimetastatic effect of MSC has been observed
in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic effect
of MSC--besides the immune-reconstitution--may also be due to its cell adhesion
inhibitory, cell proliferation inhibitory, apoptosis enhancing, and antioxidant
characteristics, also observed in our in vitro experiments. It is even more
noteworthy that combined treatment with MSC and one of the following antineoplastic
agents (5-FU and DTIC)--both in wide use in every day clinical practice--exhibited
a significantly enhanced antimetastatic effect in appropriate metastasis
models (established from C38 mouse colon carcinoma and B16 mouse melanoma
respectively) as compared to the effect elicited by any component of these
therapeutic compositions (MSC + 5-FU and MSC + DTIC) administered alone.
The results show that the fermented wheat germ extract (MSC) has more than
an additive effect and synergistically enhanced the metastasis inhibitory
effect of both antineoplastic agents studied till now. It is also worthy
of mention that the synchronous treatment with MSC profoundly decreased the
toxic side effects of the applied antineoplastic agents (decreased weight
loss etc). Based on the biological effects of MSC--shown to be non-toxic
by subacute toxicology studies--this product may be used as an adjuvant in
the therapy of malignant neoplasia and other diseases caused by or following
immune-deficiency.
Hwang, J. T., J. Ha, et al. (2007). "Apoptotic effect
of EGCG in HT-29 colon cancer cells via AMPK signal pathway." Cancer Lett
247(1): 115-21.
EGCG [(-)epigallocatechin-3-gallate], a green tea-derived
polyphenol, has been shown to suppress cancer cell proliferation, and interfere
with the several signaling pathways and induce apoptosis. Practically, there
is emerging evidence that EGCG has a potential to increase the efficacy of
chemotherapy in patients. We hypothesized that EGCG may exert cell cytotoxicity
through modulating AMPK (AMP-activated protein kinase) followed by the decrease
in COX-2 expression. EGCG treatment to colon cancer cells resulted in a strong
activation of AMPK and an inhibition of COX-2 expression. The decreased COX-2
expression as well as prostaglandin E(2) secretion by EGCG was completely
abolished by inhibiting AMPK by an AMPK inhibitor, Compound C. Also, the
activation of AMPK was accompanied with the reduction of VEGF (vascular endothelial
growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells.
These findings support the regulatory role of AMPK in COX-2 expression in
EGCG-treated cancer cells. Furthermore, we have found that reactive oxygen
species (ROS) is an upstream signal of AMPK, and the combined treatment of
EGCG and chemotherapeutic agents, 5-FU or Etoposide, exert a novel therapeutic
effect on chemo-resistant colon cancer cells. AMPK, a molecule of newly defined
cancer target, was shown to control COX-2 in EGCG-treated colon cancer cells.
Hwang, J. T., J. Ha, et al. (2005). "Combination of 5-fluorouracil and genistein
induces apoptosis synergistically in chemo-resistant cancer cells through
the modulation of AMPK and COX-2 signaling pathways." Biochem Biophys Res
Commun 332(2): 433-40.
5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic
drugs targeting various cancers, but its chemo-resistance remains as a major
obstacle in clinical settings. In the present study, HT-29 colon cancer cells
were markedly sensitized to apoptosis by both 5-FU and genistein compared
to the 5-FU treatment alone. There is an emerging evidence that genistein,
soy-derived phytoestrogen, may have potential as a chemotherapeutic agent
capable of inducing apoptosis or suppressing tumor promoting proteins such
as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity
of genistein is not known. The present study focused on the correlation of
AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK
is known as a primary cellular homeostasis regulator and a possible target
molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic
molecule. Our results demonstrated that the combination of 5-FU and genistein
abolished the up-regulated state of COX-2 and prostaglandin secretion caused
by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed
by the specific activation of AMPK and the up-regulation of p53, p21, and
Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU
was diminished by the combination treatment with 5-FU and genistein. Furthermore,
the reactive oxygen species (ROS) was found as an upstream signal for AMPK
activation by genistein. These results suggested that the combination of
5-FU and genistein exert a novel chemotherapeutic effect in colon cancers,
and AMPK may be a novel regulatory molecule of COX-2 expression, further
implying its involvement in cytotoxicity caused by genistein.
Hwang, J. T.,
Y. M. Kim, et al. (2006). "Selenium regulates cyclooxygenase-2 and extracellular
signal-regulated kinase signaling pathways by activating AMP-activated protein
kinase in colon cancer cells." Cancer Res 66(20): 10057-63.
Epidemiologic
and experimental evidences indicate that selenium, an essential trace element,
can reduce the risk of a variety of cancers. Protection against certain types
of cancers, particularly colorectal cancers, is closely associated with pathways
involving cyclooxygenase-2 (COX-2). We found that AMP-activated protein kinase
(AMPK), which functions as a cellular energy sensor, mediates critical anticancer
effects of selenium via a COX-2/prostaglandin E(2) signaling pathway. Selenium
activated AMPK in tumor xenografts as well as in colon cancer cell lines,
and this activation seemed to be essential to the decrease in COX-2 expressions.
Transduction with dominant-negative AMPK into colon cancer cells or application
of cox-2(-/-)-negative cells supported the evidence that AMPK is an upstream
signal of COX-2 and inhibits cell proliferation. In HT-29 colon cancer cells,
carcinogenic agent 12-O-tetradecanoylphorbol-13-acetate (TPA) activated extracellular
signal-regulated kinase (ERK) that led to COX-2 expression and selenium blocked
the TPA-induced ERK and COX-2 activation via AMPK. We also showed the role
of a reactive oxygen species as an AMPK activation signal in selenium-treated
cells. We propose that AMPK is a novel and critical regulatory component
in selenium-induced cancer cell death, further implying AMPK as a prime target
of tumorigenesis.
Ichikawa, D., T. Takahashi, et al. (1998). "[Postoperative
management of the preserved rectal segment in patients with familial polyposis:
the use of 5-fluorouracil suppositories and green tea extract to inhibit
tumor growth]." Nippon Geka Gakkai Zasshi 99(6): 391-5.
We report the clinical
details of seven patients with familial polyposis. They underwent subtotal
colectomy with ileorectostomy, and were treated with 5-fluorouracil suppositories
and green tea extract after surgery. Some regression of the polyps in the
preserved rectal segment was observed, and no rectal cancer developed in
any of these patients.
Jaiswal, A. S., B. P. Marlow, et al. (2002). "Beta-catenin-mediated
transactivation and cell-cell adhesion pathways are important in curcumin
(diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells." Oncogene
21(55): 8414-27.
The development of nontoxic natural agents with chemopreventive
activity against colon cancer is the focus of investigation in many laboratories.
Curcumin (feruylmethane), a natural plant product, possesses such chemopreventive
activity, but the mechanisms by which it prevents cancer growth are not well
understood. In the present study, we examined the mechanisms by which curcumin
treatment affects the growth of colon cancer cells in vitro. Results showed
that curcumin treatment causes p53- and p21-independent G(2)/M phase arrest
and apoptosis in HCT-116(p53(+/+)), HCT-116(p53(-/-)) and HCT-116(p21(-/-))
cell lines. We further investigated the association of the beta-catenin-mediated
c-Myc expression and the cell-cell adhesion pathways in curcumin-induced
G(2)/M arrest and apoptosis in HCT-116 cells. Results described a caspase-3-mediated
cleavage of beta-catenin, decreased transactivation of beta-catenin/Tcf-Lef,
decreased promoter DNA binding activity of the beta-catenin/Tcf-Lef complex,
and decreased levels of c-Myc protein. These activities were linked with
decreased Cdc2/cyclin B1 kinase activity, a function of the G(2)/M phase
arrest. The decreased transactivation of beta-catenin in curcumin-treated
HCT-116 cells was unpreventable by caspase-3 inhibitor Z-DEVD-fmk, even though
the curcumin-induced cleavage of beta-catenin was blocked in Z-DEVD-fmk pretreated
cells. The curcumin treatment also induced caspase-3-mediated degradation
of cell-cell adhesion proteins beta-catenin, E-cadherin and APC, which were
linked with apoptosis, and this degradation was prevented with the caspase-3
inhibitor. Our results suggest that curcumin treatment impairs both Wnt signaling
and cell-cell adhesion pathways, resulting in G(2)/M phase arrest and apoptosis
in HCT-116 cells.
Jordan, A. and J. Stein (2003). "Effect of an omega-3 fatty
acid containing lipid emulsion alone and in combination with 5-fluorouracil
(5-FU) on growth of the colon cancer cell line Caco-2." Eur J Nutr 42(6):
324-31.
BACKGROUND: In this study we examined the effects of a fish oil-based
lipid emulsion (FO) rich in omega-3 fatty acids, which is used in humans
as a component of parenteral nutrition, on the growth of the colon cancer
cell line Caco-2. AIM OF THE STUDY: The aim of the present study was to investigate
whether the FO influences growth and chemosensitivity of the colon cancer
cell line Caco-2. FO was tested alone and in combination with the anticancer
drug 5-fluorouracil (5-FU). METHODS: Cell numbers were determined with crystal
violet staining, cell cycle distribution was assessed using a flow cytometer
and apoptosis was visualized by staining nuclei with diamino-phenylindole
hydrochloride. RESULTS: FO inhibited growth of Caco-2 cells in a time and
dose dependent manner. FO treatment evoked apoptosis as confirmed by cell
morphology. Cell cycle analysis identified an accumulation of cells in the
G(2)/M phase after incubation with FO. The combined treatment of the cells
with FO and 5-FU resulted in a significant enhancement of the growth inhibition
seen after exposure to either substance alone. Treatment of the cells with
5-FU specifically blocked the cell cycle in the S phase. The combined treatment
of 5-FU with FO showed a further increase in the accumulation of cells in
the S phase. CONCLUSIONS: In conclusion, FO has a potent antiproliferative
effect on Caco-2 cells, at least in part, due to a decrease in the progression
of the cell cycle and the induction of apoptosis. The combination of FO with
5-FU results in an additive growth inhibitory effect.
Katoh, R. and M. Ooshiro
(2007). "Enhancement of antitumor effect of tegafur/uracil (UFT) plus leucovorin
by combined treatment with protein-bound polysaccharide, PSK, in mouse models." Cell
Mol Immunol 4(4): 295-9.
We evaluated the antitumor effect of combined therapy
with tegafur/uracil (UFT) plus leucovorin (LV) (UFT/LV) and protein-bound
polysaccharide, PSK, in three mouse models of transplantable tumors. UFT/LV
showed antitumor effect against Meth A sarcoma, and the antitumor effect
was enhanced when PSK given concomitantly. UFT/LV showed antitumor effect
to Lewis lung carcinoma and PSK alone also showed antitumor effect at high
dose, but a combination of UFT/LV and PSK resulted in no enhanced antitumor
effect. Colon 26 carcinoma was weakly responsive to UFT/LV, and no enhancement
of antitumor effect was found even PSK was used in combination. In conclusion,
while the effect of PSK varies depending on tumor, combined use of UFT/LV
and PSK may be expected to augment the antitumor effect.
Kim, K. H., H. Y.
Park, et al. (2005). "[The inhibitory effect of curcumin on the growth of
human colon cancer cells (HT-29, WiDr) in vitro]." Korean J Gastroenterol
45(4): 277-84.
BACKGROUND/AIMS: The effects of curcumin on the growth of
human colon cancer cell lines, HT-29 and WiDr cells were examined and the
effects of 5-fluorouracil (5-FU) were also studied. METHODS: The growth of
HT-29 and WiDr cells were examined by counting cell number on two and four
days treatment with 1-40 microm of curcumin, and 0.1 microg/mL, 0.3 microg/mL
of 5-FU. The reversibility of curcumin was examined on one day to seven days
treatment with 10 microm curcumin after seeding to 2 x 10(4) cells/well.
To examine the inhibitory effects of curcumin, cell cycle analysis was done
on the HT-29 cells after four days treatment with 20 microm curcumin. RESULTS:
Curcumin inhibited the growth of HT-29 and WiDr cells in a dose-dependent
fashion. The growth rate of the group in which curcumin was removed by media
change 24 hours after the treatment of curcumin was not different from that
of control group. Curcumin combined with 5-FU markedly inhibited the growth
of HT-29 and WiDr cells compared to curcumin or 5-FU alone. After four days
treatment of HT-29 cells with 20 microm curcumin, the fraction of cells in
G2-M phase was 35.3% in curcumin group, much higher than 13.8% of the control
group. CONCLUSIONS: Curcumin significantly inhibited the growth of HT-29
and WiDr cells in a dose-dependent, reversible fashion.
Kim, Y. M., J. T.
Hwang, et al. (2007). "Involvement of AMPK signaling cascade in capsaicin-induced
apoptosis of HT-29 colon cancer cells." Ann N Y Acad Sci 1095: 496-503.
Adenosine
monophosphate (AMP)-activated protein kinase (AMPK) is activated during ATP-depleting
metabolic states, such as hypoxia, heat shock, oxidative stress, and exercise.
As a highly conserved heterotrimeric kinase that functions as a major metabolic
switch to maintain energy homeostasis, AMPK has been shown to exert as an
intrinsic regulator of mammalian cell cycle. Moreover, AMPK cascade has emerged
as an important pathway implicated in cancer control. In this article, we
have investigated the effects of capsaicin on apoptosis in relation to AMPK
activation in colon cancer cell. Capsaicin-induced apoptosis was revealed
by the presence of nucleobodies in the capsaicin-treated HT-29 colon cancer
cells. Concomitantly, the activation of AMPK and the increased expression
of the inactive form of acetyl-CoA carboxylase (ACC) were detected in capsaicin-treated
colon cancer cells. We showed that both capsaicin and 5'-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside
(AICAR), an AMPK activator possess the AMPK-activating capacity as well as
apoptosis-inducing properties. Evidence of the association between AMPK activation
and the increased apoptosis in HT-29 colon cancer cells by capsaicin treatment,
and further findings of the correlation of the activated AMPK and the elevated
apoptosis by cotreatment of AICAR and capsaicin support AMPK as an important
component of apoptosis, as well as a possible target of cancer control.
Kitajima,
M., Y. Ikeda, et al. (1987). "[The effect of tegafur suppository and glutathione
in patients with gastric and colonic cancer with special reference to the
histopathological anticancer effect]." Gan To Kagaku Ryoho 14(11): 3131-9.
The purpose of these studies is to evaluate the anticancerous effects of
tegafur suppository and Glutathione (GSH) as enhanced drug and compare the
difference of the histopathological effects and tissue concentration of 5-FU
and FT-207 in gastric and colon cancer. Thirty three patients with gastric
cancer and 17 with colon cancer were treated by tegafur suppository at a
dose of 1,500 mg/day and GSH, 1,200 mg/day intravenously. These patients
were clinically divided into two groups, one of which was treated with tegafur
suppository (Group A) and another administered with suppository and GSH (Group
B). Five-fluorouracil was measured by GC-MF method and FT-207 was also done
by HPLC method. After surgery, relationship between tissue concentration
of 5-FU and histopathological effects were investigated. In gastric cancer,
5-FU concentration in cancer tissue was significantly kept high level in
cancer tissue in patients treated with tegafur and GSH (Group B). However,
there was no same results in colon cancer. These results seemed to be the
difference of organ specificity. According to histopathological studies,
well differentiated adenocarcinoma including papillary carcinoma were markedly
effective compared to poorly differentiated adenocarcinoma in both cancer.
This difference of anticancerous effect was supposed to be microangiographically
different of microvascular architecture and quantity of anticancerous agents
in tumor.
Kokura, S., N. Yoshida, et al. (2005). "The radical scavenger edaravone
enhances the anti-tumor effects of CPT-11 in murine colon cancer by increasing
apoptosis via inhibition of NF-kappaB." Cancer Lett 229(2): 223-33.
The transcription
factor NF-kappaB is reportedly activated by anti-cancer chemotherapeutic
compounds in many cancer cell lines and NF-kappaB activation is one mechanism
by which tumors become resistant to apoptosis. Antioxidants have been reported
to serve as potent NF-kB inhibitors. In this study, we investigated the ability
of edaravone to enhance apoptosis induced by CPT-11 through inhibition of
NF-kB. In vitro, SN38, the active metabolite of CPT-11, induced activation
of NF-kB, the production of intracellular reactive oxygen species, the activation
of caspase-3, and apoptosis in colon26 cells. Pretreatment with edaravone
scavenged the SN38-produced reactive oxygen species, and inhibited the SN38-induced
activation of NF-kB. Moreover, edaravone enhanced the activation of caspase-3,
and the level of apoptosis induced by SN38. In vivo, the combination of edaravone
with CPT-11 reduced subcutaneous tumor growth and number of pulmonary metastases
more effectively than CPT-11 alone. These results demonstrate that the combination
of edaravone with CPT-11 may constitute a new strategy for treating primary
and metastatic colon cancer.
Kurokawa, H., K. Nishio, et al. (1997). "Effect
of glutathione depletion on cisplatin resistance in cancer cells transfected
with the gamma-glutamylcysteine synthetase gene." Jpn J Cancer Res 88(2):
108-10.
Lee, C. H., Y. T. Jeon, et al. (2007). "NF-kappaB as a potential
molecular target for cancer therapy." Biofactors 29(1): 19-35.
Nuclear factor
kappaB (NF-kappaB), a transcription factor, plays an important role in carcinogenesis
as well as in the regulation of immune and inflammatory responses. NF-kappaB
induces the expression of diverse target genes that promote cell proliferation,
regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis.
Furthermore, many cancer cells show aberrant or constitutive NF-kappaB activation
which mediates resistance to chemo- and radio-therapy. Therefore, the inhibition
of NF-kappaB activation and its signaling pathway offers a potential cancer
therapy strategy. In addition, recent studies have shown that NF-kappaB can
also play a tumor suppressor role in certain settings. In this review, we
focus on the role of NF-kappaB in carcinogenesis and the therapeutic potential
of targeting NF-kappaB in cancer therapy.
Lee, C. S., S. Y. Park, et al.
(2004). "Effect of change in cellular GSH levels on mitochondrial damage
and cell viability loss due to mitomycin c in small cell lung cancer cells." Biochem
Pharmacol 68(9): 1857-67.
Luo, Z., A. K. Saha, et al. (2005). "AMPK, the
metabolic syndrome and cancer." Trends Pharmacol Sci 26(2): 69-76.
The fuel-sensing
enzyme 5'-AMP-activated protein kinase (AMPK) has a major role in the regulation
of cellular lipid and protein metabolism in response to stimuli such as exercise,
changes in fuel availability and the adipocyte-derived hormones leptin and
adiponectin. Recent studies indicate that abnormalities in cellular lipid
metabolism are involved in the pathogenesis of the metabolic syndrome, possibly
because of dysregulation of AMPK and malonyl-CoA, a closely related molecule.
As we discuss in this article, several findings also point to a link between
AMPK and the growth and/or survival of some cancer cells. Thus, it has been
demonstrated recently that the tumor suppressor LKB1 is a kinase that has
a major role in phosphorylating and activating AMPK, and that another tumor
suppressor, tuberous sclerosis complex 2, is phosphorylated and activated
by AMPK. In addition, other studies indicate that mammalian homolog of target
of rapamycin (mTOR), which has been implicated in the pathogenesis of insulin
resistance and many types of cancer, is inhibited by AMPK.
Maddika, S., S.
R. Ande, et al. (2007). "Cell survival, cell death and cell cycle pathways
are interconnected: implications for cancer therapy." Drug Resist Updat 10(1-2):
13-29.
The partial cross-utilization of molecules and pathways involved in
opposing processes like cell survival, proliferation and cell death, assures
that mutations within one signaling cascade will also affect the other opposite
process at least to some extent, thus contributing to homeostatic regulatory
circuits. This review highlights some of the connections between opposite-acting
pathways. Thus, we discuss the role of cyclins in the apoptotic process,
and in the regulation of cell proliferation. CDKs and their inhibitors like
the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the
Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown
both in the context of proliferation regulators and as contributors to the
apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax,
Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted
both for their apoptosis-regulating capacity and also for their effect on
the cell cycle progression. The PI3-K/Akt cell survival pathway is shown
as regulator of cell metabolism and cell survival, but examples are also
provided where aberrant activity of the pathway may contribute to the induction
of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving
complex and as apoptosis-sensitizers. We also discuss multifunctional proteins
like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition
and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches
that would involve redirecting over-active survival and proliferation pathways
towards induction of apoptosis in cancer cells.
Mamiya, N., T. Kono, et al.
(2007). "[A case of neurotoxicity reduced with goshajinkigan in modified
FOLFOX6 chemotherapy for advanced colon cancer]." Gan To Kagaku Ryoho 34(8):
1295-7.
In performing FOLFOX (infusional 5-FU/LV with oxaliplatin) for advanced
colorectal cancer, neurotoxicity of oxaliplatin (L-OHP) is the serious dose
limiting factor. On the other hand, goshajinkigan is recently considered
as an effective agent for the neurotoxicity of taxanes in Japan.We have applied
goshajinkigan (TJ 107) for a case of advanced colon cancer with mFOLFOX 6,
and experienced a reduction in numbness, the adverse effect of LOHP. A 57-year-old
woman with descending colon cancer (H 1, P 3, Stage IV) underwent hemicolectomy
D 2, rt.colectomy, bilateral oophorectomy, cholecystectomy and transverse
colonostomy. After operation, mFOLFOX 6 was applied. In order to reduce the
neurotoxicity of L-OHP, TJ 107 was used together from the third course. The
severities of neurotoxicity before and after administration of TJ 107 were
grade 2 and 1,respectively. TJ 107 could reduce or prevent the neurotoxicity
of L-OHP.
Mans, D. R., G. J. Schuurhuis, et al. (1992). "Modulation by D,L-buthionine-S,R-sulphoximine
of etoposide cytotoxicity on human non-small cell lung, ovarian and breast
carcinoma cell lines." Eur J Cancer 28A(8-9): 1447-52.
Meijer, C., N. H.
Mulder, et al. (1990). "The role of glutathione in resistance to cisplatin
in a human small cell lung cancer cell line." Br J Cancer 62(1):
72-7.
Nadal,
J. C., C. J. van Groeningen, et al. (1989). "Schedule-dependency of in vivo
modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma." Invest
New Drugs 7(2-3): 163-72.
The effect of leucovorin (LV) given in various
doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil
(5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively
resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and
C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum
tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous
administration of 5FU and LV nor 5FU combined with delayed administration
of LV potentiated the antitumor activity of 5FU. LV given twice - 1 hr before
(50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) - gave significantly
better delay of tumor growth of both tumor lines than 5FU did alone (100
mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg.
Delayed administration of uridine (3500 mg/kg) allowed the use of higher
5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity
led to moderate weight loss in treated mice, but was comparable for mice
treated with 5FU alone or combined with LV. Hematological toxicity consisted
of moderate leukopenia (nadir 40%), which was observed with the most active
schedule and was less severe than with 5FU alone. This schedule did not cause
thrombocytopenia, but after discontinuation the thrombocyte count showed
an overshoot. Addition of uridine to this schedule reduced hematological
toxicity only slightly. It is concluded that LV potentiated the antitumor
activity of 5FU against two solid tumor lines, i.e., a relatively resistant
and a sensitive murine colon carcinoma, and that toxicity was moderate.
Nakagawa,
Y., M. Iinuma, et al. (2007). "Characterized mechanism of alpha-mangostin-induced
cell death: caspase-independent apoptosis with release of endonuclease-G
from mitochondria and increased miR-143 expression in human colorectal cancer
DLD-1 cells." Bioorg Med Chem 15(16): 5620-8.
alpha-Mangostin, a xanthone
from the pericarps of mangosteen (Garcinia mangostana Linn.), was evaluated
for in vitro cytotoxicity against human colon cancer DLD-1 cells. The number
of viable cells was consistently decreased by the treatment with alpha-mangostin
at more than 20 microM. The cytotoxic effect of 20 microM alpha-mangostin
was found to be mainly due to apoptosis, as indicated by morphological findings.
Western blotting, the results of an apoptosis inhibition assay using caspase
inhibitors, and the examination of caspase activity did not demonstrate the
activation of any of the caspases tested. However, endonuclease-G released
from mitochondria with the decreased mitochondrial membrane potential was
shown. The levels of phospho-Erk1/2 were increased in the early phase until
1h after the start of treatment and thereafter decreased, and increased again
in the late phase. On the other hand, the level of phospho-Akt was sharply
reduced with the process of apoptosis after 6h of treatment. Interestingly,
the level of microRNA-143, which negatively regulates Erk5 at translation,
gradually increased until 24h following the start of treatment. We also examined
the synergistic growth suppression in DLD-1 cells by the combined treatment
of the cells with alpha-mangostin and 5-FU which is one of the most effective
chemotherapeutic agents for colorectal adenocarcinoma. The co-treatment with
alpha-mangostin and 5-FU, both at 2.5 microM, augmented growth inhibition
compared with the treatment with 5 microM of alpha-mangostin or 5 microM
5-FU alone. These findings indicate unique mechanisms of alpha-mangostin-induced
apoptosis and its action as an effective chemosensitizer.
Pai, R., T. Nakamura,
et al. (2003). "Prostaglandins promote colon cancer cell invasion; signaling
by cross-talk between two distinct growth factor receptors." Faseb J 17(12):
1640-7.
Colorectal cancer is the second most frequent cancer in the Western
world, often lethal when invasion and/or metastasis occur. In addition to
hepatocyte growth factor (HGF), colon cancer invasion may be driven by prostaglandins,
especially the E2 series (PGE2), generated by the cyclooxygenase-2 (Cox-2)
enzyme. While concentration of PGE2 as well as expression of Cox-2, HGF receptor
(c-Met-R), epidermal growth factor receptor (EGFR), and beta-catenin are
all dramatically increased in colon cancers and implicated in their growth
and invasion, the precise role of PGE2 in the latter process remains unclear.
Here we provide evidence that PGE2 transactivates c-Met-R (contingent upon
functional EGFR), increases tyrosine phosphorylation and nuclear accumulation
of beta-catenin, and induces urokinase-type plasminogen activator receptor
(uPAR) mRNA expression. This is accompanied by increased beta-catenin association
with c-Met-R and enhanced colon cancer cell invasiveness. Inactivation of
EGFR and c-Met-R significantly reduced PGE2-induced cancer cell invasiveness.
Clinical relevance of these findings is confirmed by our immunohistochemical
studies demonstrating that cancer cells in the invasive front overexpress
Cox-2, c-Met-R, and beta-catenin. Our findings explain a functional relationship
between prostaglandins, EGFR, and c-Met-R in colon cancer growth and invasion.
Patel, B. B., R. Sengupta, et al. (2008). "Curcumin enhances the effects
of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon
cancer cells by modulating EGFR and IGF-1R." Int J Cancer 122(2): 267-73.
Curcumin (diferuloylmethane), which has been shown to inhibit growth of
transformed cells, has no discernible toxicity and achieves high levels
in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX)
remains the backbone of colorectal cancer chemotherapeutics, but with limited
success. The present investigation was, therefore, undertaken to examine
whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen
will be a superior therapeutic strategy for colorectal cancer. Indeed,
results of our in vitro studies demonstrated that curcumin together with
FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001)
of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU,
curcumin + 5-FU or FOLFOX. These changes were associated with decreased
expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3
(72-100%) and IGF-1R (67%) as well as their downstream effectors such as
Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced
a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3),
curcumin together with FOLFOX caused a 5-fold increase in the same, when
compared to controls. This in turn led to increased sequestration of IGF
by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of
IGF-1R. We conclude that the superior effects of the combination therapy
of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling
pathways. We also suggest that inclusion of curcumin to the conventional
chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy
for colorectal cancer.
Perumal, S. S., P.
Shanthi, et al. (2005). "Augmented efficacy of tamoxifen in rat breast tumorigenesis
when gavaged along with riboflavin, niacin, and CoQ10: effects on lipid peroxidation
and antioxidants in mitochondria." Chem Biol Interact 152(1): 49-58.
Porter,
A. G. and R. U. Janicke (1999). "Emerging roles of caspase-3 in apoptosis." Cell
Death Differ 6(2): 99-104.
Caspases are crucial mediators of programmed cell
death (apoptosis). Among them, caspase-3 is a frequently activated death
protease, catalyzing the specific cleavage of many key cellular proteins.
However, the specific requirements of this (or any other) caspase in apoptosis
have remained largely unknown until now. Pathways to caspase-3 activation
have been identified that are either dependent on or independent of mitochondrial
cytochrome c release and caspase-9 function. Caspase-3 is essential for normal
brain development and is important or essential in other apoptotic scenarios
in a remarkable tissue-, cell type- or death stimulus-specific manner. Caspase-3
is also required for some typical hallmarks of apoptosis, and is indispensable
for apoptotic chromatin condensation and DNA fragmentation in all cell types
examined. Thus, caspase-3 is essential for certain processes associated with
the dismantling of the cell and the formation of apoptotic bodies, but it
may also function before or at the stage when commitment to loss of cell
viability is made.
Press, M. F. and H. J. Lenz (2007). "EGFR, HER2 and VEGF
pathways: validated targets for cancer treatment." Drugs 67(14): 2045-75.
Targeted therapies are rationally designed to interfere with specific molecular
events that are important in tumour growth, progression or survival. Several
targeted therapies with anti-tumour activity in human cancer cell lines and
xenograft models have now been shown to produce objective responses, delay
disease progression and, in some cases, improve survival of patients with
advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal
growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib,
EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR
type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of
both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular
endothelial growth factor (VEGF) monoclonal antibody.On the basis of preclinical
and clinical evidence, EGFR, HER2 and VEGF represent validated targets for
cancer therapy and remain the subject of intensive investigation. Both EGFR
and HER2 are targets found on cancer cells, whereas VEGF is a target that
acts in the tumour microenvironment. Clinical studies are focusing on how
to best incorporate targeted therapy into current treatment regimens and
other studies are exploring whether different strategies for inhibiting these
targets will offer greater benefit. It is clear that optimal use of targeted
therapy will depend on understanding how these drugs work mechanistically,
and recognising that their activities may differ across patient populations,
tumour types and disease stages, as well as when and how they are used in
cancer treatment. The results achieved with targeted therapies to date are
promising, although they illustrate the need for additional preclinical and
clinical study.
Robson, S., S. Pelengaris, et al. (2006). "c-Myc and downstream
targets in the pathogenesis and treatment of cancer." Recent Patents Anticancer
Drug Discov 1(3): 305-26.
The c-Myc oncoprotein is a master regulator of
genes involved in diverse cellular processes. Situated upstream of signalling
pathways regulating cellular replication/growth as well as apoptosis/growth
arrest, c-Myc may help integrate processes determining cell numbers and tissue
size in physiology and disease. In cancer, this 'dual potential' allows c-Myc
to act as its own tumour suppressor. Evidently, given that deregulated expression
of c-Myc is present in most, if not all, human cancers (Table 1) and is associated
with a poor prognosis, by implication these in-built 'failsafe' mechanisms
have been overcome. To explore the complex activity of c-Myc and its potential
as a therapeutic target 'post-genome era' technologies for determining global
gene expression alongside advanced new models for the study of tumourigenesis
in vivo have proved invaluable. Thus, many recent studies have provided encouragement
for the therapeutic targeting of c-Myc in cancer and have revealed new protein
targets for manipulating aspects of c-Myc activity. The remarkable regression
of even advanced and genetically unstable tumours, seen following deactivation
of c-Myc in various models is particularly exciting. This review will discuss
what is known about the role of c-Myc in growth deregulation and cancer and
will conclude with a discussion of the most promising recent developments
in Myc-targeted therapeutics.
Rupnarain, C., Z. Dlamini, et al. (2004). "Colon
cancer: genomics and apoptotic events." Biol Chem 385(6): 449-64.
Colon cancer
is the third most common cancer globally. The risk of developing colon cancer
is influenced by a number of factors that include age and diet, but is primarily
a genetic disease, resulting from oncogene over-expression and tumour suppressor
gene inactivation. The induction and progression of the disease is briefly
outlined, as are the cellular changes that occur in its progression. While
colon cancer is uniformly amenable to surgery if detected at the early stages,
advanced carcinomas are usually lethal, with metastases to the liver being
the most common cause of death. Oncogenes and genetic mutations that occur
in colon cancer are featured. The molecules and signals that act to eradicate
or initiate the apoptosis cascade in cancer cells, are elucidated, and these
include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide,
butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon
cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies
aimed at controlling colon cancer are reviewed briefly.
Scagliotti, G. V.
and S. Novello (2003). "Pemetrexed and its emerging role in the treatment
of thoracic malignancies." Expert Opin Investig Drugs 12(5): 853-63.
Pemetrexed
(Alimta); Eli Lilly and Co., Indianapolis, IN, USA) is a unique multitargeted
antifolate that inhibits at least three enzymes, thymidylate synthase, dihydrofolate
reductase and glycinamide ribonucleotide formyltransferase. This novel drug
is being evaluated in a comprehensive clinical programme for use in both
front-line and second-line therapies. It has shown broad activity in a number
of solid tumours, including colon cancer, breast cancer, lung cancer, head
and neck, cervical cancer and others. While a number of antifolates have
been evaluated in clinical trials, further development has been stopped or
delayed by the occurrence of life-threatening toxicities. Similar trends
were also initially observed with pemetrexed as well, but investigators later
showed that these toxicities could be minimised with folic acid and vitamin
B(12) supplementation included in the treatment regimen. Preliminary data
indicate that this supplementation does not hamper drug efficacy in most
tumour types and in many cases, supplemented patients exhibit improved clinical
outcome. Here, the current data for pemetrexed in treating thoracic malignancies
are reviewed, with special focus on malignant pleural mesothelioma and non-small
cell lung cancer.
Schmittgen, T. D., A. Koolemans-Beynen, et al. (1992). "Effects
of 5-fluorouracil, leucovorin, and glucarate in rat colon-tumor explants." Cancer
Chemother Pharmacol 30(1): 25-30.
In a previous study, we showed that 5-fluorouracil
(FU) is active against the dimethylhydrazine-induced colon tumor in rats;
a 7-day infusion of FU at 30 mg/kg daily produced 85% tumor-free cures. The
present study examined the effects of FU alone and in combination with leucovorin
(LV) or D-glucarate (GT) using an ex vivo system that maintained the growth
of the rat colon-tumor explants on collagen gels. The labeling index (LI)
was determined by the incorporation of [3H]-thymidine and autoradiography.
The mean LI of the untreated control was 64.8% +/- 19.8%. The IC50, IC90,
and IC95 values following a 7-day exposure to FU were 0.36, 0.75, and 1.22
microM, respectively. In comparison, the steady-state FU concentration required
to produce 67% tumor-free cures in rats following a 7-day infusion is 1.54
microM. LV alone did not produce any antiproliferative effect at concentrations
as high as 10 microM. The addition of LV at concentrations of 0.001-10 microM
did not significantly reduce the IC50 of FU. The lack of effect of LV may
have been due to tissue saturation with folate provided in the culture medium.
GT alone reduced the tumor LI by 20%-30% at concentrations of 0.1-10 microM.
GT enhanced the effect of FU. As compared with FU alone, the addition of
GT at concentrations of 0.1 and 1.0 microM reduced the IC50 of FU by 47%
and 60% to 0.21 and 0.16 microM, respectively. Assessment of the potentiation
of the inhibitory effect of FU by GT using two-way analysis of variance and
the isobologram method indicated a significant synergistic interaction between
FU and GT. This interaction occurred within the FU concentration range of
0.08 and 0.4 microM. In summary, these data indicate that (a) the IC values
for FU are comparable in tumor explants and in rats, suggesting that the
effects in cultured tumors reflect those in intact animals; (b) GT alone
showed antitumor activity, albeit relatively minor as compared with FU; (c)
FU and GT exhibited synergistic activity, which was most pronounced at FU
concentrations that produced submaximal activity (less than 30% inhibition
of tumor LI); and (d) GT and LV had different effects on the growth inhibition
by FU, suggesting that GT acts by a mechanism different from the thymidylate
synthase-directed effect of FU and LV.
Sethi, G., B. Sung, et al. (2008). "Nuclear
factor-kappaB activation: from bench to bedside." Exp Biol Med (Maywood)
233(1): 21-31.
Nuclear factor-kappaB (NF-kappaB) is a proinflammatory transcription
factor that has emerged as an important player in the development and progression
of malignant cancers. NF-kappaB targets genes that promote tumor cell proliferation,
survival, metastasis, inflammation, invasion, and angiogenesis. Constitutive
or aberrant activation of NF-kappa is frequently encountered in many human
tumors and is associated with a resistant phenotype and poor prognosis. The
mechanism of such persistent NF-kappaB activation is not clear but may involve
defects in signaling pathways, mutations, or chromosomal rearrangements.
Suppression of constitutive NF-kappaB activation inhibits the oncogenic potential
of transformed cells and thus makes NF-kappaB an interesting new therapeutic
target in cancer.
Shaw, R. J., M. Kosmatka, et al. (2004). "The tumor suppressor
LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis
in response to energy stress." Proc Natl Acad Sci U S A 101(10): 3329-35.
AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular
energy status found in all eukaryotic cells. AMPK is activated by stimuli
that increase the cellular AMP/ATP ratio. Essential to activation of AMPK
is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity
in mammalian cells has remained elusive. Here we present biochemical and
genetic evidence indicating that the LKB1 serine/threonine kinase, the gene
inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant
regulator of AMPK activation in several mammalian cell types. We show that
LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates
its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly
complete loss of Thr-172 phosphorylation and downstream AMPK signaling in
response to a variety of stimuli that activate AMPK. Reintroduction of WT,
but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore,
we show that LKB1 plays a biologically significant role in this pathway,
because LKB1-deficient cells are hypersensitive to apoptosis induced by energy
stress. On the basis of these results, we propose a model to explain the
apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1
are resistant to cell transformation by conventional oncogenes and are sensitive
to killing in response to agents that elevate AMP. The role of LKB1/AMPK
in the survival of a subset of genetically defined tumor cells may provide
opportunities for cancer therapeutics.
Sibilia, M., R. Kroismayr, et al.
(2007). "The epidermal growth factor receptor: from development to tumorigenesis." Differentiation
75(9): 770-87.
The epidermal growth factor receptor (EGFR) is activated by
many ligands and belongs to a family of tyrosine kinase receptors, including
ErbB2, ErbB3, and ErbB4. These receptors are de-regulated in many human tumors,
and EGFR amplification, overexpression, and mutations are detected at a high
frequency in carcinomas and glioblastomas, which are tumors of epithelial
and glial origin, respectively. From the analysis of EGFR-deficient mice,
it seems that the cell types mostly affected by the absence of EGFR are epithelial
and glial cells, the same cell types where the EGFR is found to be overexpressed
in human tumors. Therefore, it is important to define molecularly the function
of EGFR signaling in the development of these cell types, because this knowledge
will be of fundamental importance to understand how aberrant EGFR signaling
can lead to tumor formation and progression. A molecular understanding of
the pathways that control the development of a given tissue or cell type
will also provide the basis for developing better combination therapies targeting
different key components of the EGFR signaling network in the respective
cancerous cells. Here, we will review the current knowledge, mostly derived
from the analysis of genetically modified mice and cells, about the function
of the EGFR in specific organs and tissues and in sites where the EGFR is
found to be overexpressed in human tumors.
Sinicrope, F. A. (2006). "Targeting
cyclooxygenase-2 for prevention and therapy of colorectal cancer." Mol Carcinog
45(6): 447-54.
Cyclooxygenase-2 (COX-2) is an inducible enzyme that regulates
prostaglandin synthesis and is overexpressed at sites of inflammation and
in several epithelial cancers. A causal link for COX-2 in epithelial tumorigenesis
was shown in genetically manipulated animal models of colon and breast carcinoma.
Studies have elucidated the regulation of COX-2 expression and have identified
EP receptors through which prostanoids exert their biological effects. Mechanistic
studies indicated that COX-2 is involved in apoptosis resistance, angiogenesis,
and tumor cell invasiveness, which appear to contribute to its effects in
tumorigenesis. Furthermore, forced COX-2 expression has been shown to suppress
apoptosis by modulating the level of death receptor 5 (DR5) and this effect
was reversed by a COX inhibitor. COX enzymes are targets for cancer prevention
as shown by the observation that nonselective COX and selective COX-2 inhibitors
have been reported to effectively prevent experimental colon cancer and can
regress colorectal polyps in patients with familial adenomatous polyposis.
This review will focus on the role of COX-2 as a target for the prevention
and treatment of human colorectal cancer.
Sriram, N., S. Kalayarasan, et
al. (2008). "Diallyl sulfide induces apoptosis in Colo 320 DM human colon
cancer cells: involvement of caspase-3, NF-kappaB, and ERK-2." Mol Cell Biochem
311(1-2): 157-65.
Chemoprevention is regarded as one of the most promising
and realistic approaches in the prevention of human cancer. Diallyl sulfide
(DAS), an organosulfur component of garlic has been known for its chemopreventive
activities against various cancers and also in recent years, numerous investigations
have shown that sulfur-containing compounds induce apoptosis in multiple
cell lines and experimental animals. Thus the present study was focused to
elucidate the anticancerous effect and the mode of action of DAS against
Colo 320 DM colon cancer cells. DAS induced apoptosis in Colo 320 DM cells
was revealed by flow cytometer analysis and phosphatidyl serine exposure.
DAS also promoted cell cycle arrest substantially at G2/M phase in Colo 320
DM cells. The production of reactive oxygen intermediates, which were examined
by 2,7-dichlorodihydrofluorescein diacetate (H(2)DCF-DA), increased with
time, after treatment with DAS. The activities of alkaline phosphatase (ALP)
and lactate dehydrogenase (LDH) were decreased upon DAS treatment, which
shows the antiproliferative and the cytotoxic effects, respectively. The
expression of NF-kappaB was upregulated in DAS treated cells, compared to
normal cells. Further, DAS promoted the expression of caspase-3 and suppression
of Extracellular Regulatory Kinase-2 (ERK-2) activity in Colo 320 DM cells
that was determined by Western blot analysis. In conclusion, DAS increased
the production of ROS, caused cell cycle arrest, decreased cell proliferation
and induced apoptosis in Colo 320 DM cells. Thus, this study put forward
DAS as a drug that can possibly be used to treat cancers.
Sundaram, S. G.
and J. A. Milner (1996). "Diallyl disulfide suppresses the growth of human
colon tumor cell xenografts in athymic nude mice." J Nutr 126(5): 1355-61.
The present studies examined the anti-proliferative effects of diallyl
disulfide (DADS) on the growth of human colon tumor cell line, HCT-15,
xenografts in 6-wk-old female NCr nu/nu mice with an initial body weight
of 20-22 g. Intraperitoneal injection of 1 mg DADS thrice weekly reduced
tumor volume by 69% (P < 0.05)
without apparent ill consequences such as altered growth of the host. Providing
this quantity of DADS intragastrically also inhibited growth of the HCT-15
tumor. At equivalent DADS dosages, intraperitoneal treatment was proportionately
more effective (P < 0.05) in reducing tumor growth than gastric intubation.
Tumor inhibition caused by DADS (0.5 mg thrice weekly) was similar to that
occurring with 5-fluorouracil (5-FU) treatment (0.5 mg thrice weekly). Combining
DADS and 5-FU was no more effective in inhibiting tumor growth than using
either compound alone. However, concurrent DADS treatment significantly (P < 0.05)
inhibited the depression in leukocyte counts and spleen weight and prevented
the elevated plasma urea caused by 5-FU treatment. These data suggest that
DADS, a constituent of garlic oil, reduces the toxicity of 5-FU and is
an effective antitumorigenic agent against xenografts resulting from an
established human colon tumor cell line.
Takahashi, Y. and Y. Niitsu (1994). "[Glutathione
S transferases-pi]." Gan To Kagaku Ryoho 21(7): 945-51.
It has been known
that many drug resistant factors including p-glycoprotein related to anticancer
drug resistance. It is assumed that Glutathione s-transferase (GST) is one
of the resistant factors. In this present study, we examined the relationship
between GST (especially GST-pi) and drug resistance, and also possibility
of overcoming of drug resistance for GST-pi related drug resistance. We studied
whether GST-pi directly related to anticancer drug resistance by transfection
of GST-pi antisense cDNA into human colonic cancer cell line (M 7609). By
transfection, cytosolic GST-pi concentrations decreased and sensitivity for
adriamycin increased. It was confirmed that GST-pi directly related to some
anticancer drug resistance including adriamycin. Moreover, we also have found
that ketoprofen, which is an inhibitor of GST-pi activity, increased Adriamycin
sensitivity. That is, partial overcoming of drug resistance was obtained.
In future, it will be expected that GST-pi inhibitors etc are tried for overcoming
of drug resistance.
Veeravagu, A., A. R. Hsu, et al. (2007). "Vascular endothelial
growth factor and vascular endothelial growth factor receptor inhibitors
as anti-angiogenic agents in cancer therapy." Recent Patents Anticancer Drug
Discov 2(1): 59-71.
New blood vessel formation (angiogenesis) is fundamental
to the process of tumor growth, invasion, and metastatic dissemination. The
vascular endothelial growth factor (VEGF) family of ligands and receptors
are well established as key regulators of these processes. VEGF is a glycoprotein
with mitogenic activity on vascular endothelial cells. Specifically, VEGF-receptor
pathway activation results in signaling cascades that promote endothelial
cell growth, migration, differentiation, and survival from pre-existing vasculature.
Thus, the role of VEGF has been extensively studied in the pathogenesis and
angiogenesis of human cancers. Recent identification of seven VEGF ligand
variants (VEGF [A-F], PIGF) and three VEGF tyrosine kinase receptors (VEGFR-
[1-3]) has led to the development of several novel inhibitory compounds.
Clinical trials have shown inhibitors to this pathway (anti-VEGF therapies)
are effective in reducing tumor size, metastasis and blood vessel formation.
Clinically, this may result in increased progression free survival, overall
patient survival rate and will expand the potential for combinatorial therapies.
Having been first described in the 1980s, VEGF patenting activity since then
has focused on anti-cancer therapeutics designed to inhibit tumoral vascular
formation. This review will focus on patents which target VEGF-[A-F] and/or
VEGFR-[1-3] for use in anti-cancer treatment.
Versantvoort, C. H., H. J.
Broxterman, et al. (1995). "Regulation by glutathione of drug transport in
multidrug-resistant human lung tumour cell lines overexpressing multidrug
resistance-associated protein." Br J Cancer 72(1): 82-9.
Wang, C. Z., X.
Luo, et al. (2007). "Notoginseng enhances anti-cancer effect of 5-fluorouracil
on human colorectal cancer cells." Cancer Chemother Pharmacol 60(1): 69-79.
PURPOSE: Panax notoginseng is a commonly used Chinese herb. Although a
few studies have found that notoginseng shows anti-tumor effects, the effect
of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil
(5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer
that interferes with the growth of cancer cells. However, this compound has
serious side effects at high doses. In this study, using HCT-116 human colorectal
cancer cell line, we investigated the possible synergistic anti-cancer effects
between notoginseng flower extract (NGF) and 5-FU on colon cancer cells.
METHODS: The anti-proliferation activity of these modes of treatment was
evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed
by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation
effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc
and Rg3 were also analyzed. RESULTS: Both 5-FU and NGF inhibited proliferation
of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect
was slowly increased. The combined usage of 5-FU 5 microM and NGF 0.25 mg/ml,
significantly increased the anti-proliferation effect (59.4 +/- 3.3%) compared
with using the two medicines separately (5-FU 5 microM, 31.1 +/- 0.4%; NGF
0.25 mg/ml, 25.3 +/- 3.6%). Apoptotic analysis showed that at this concentration,
5-FU did not exert an apoptotic effect, while apoptotic cells induced by
NGF were observed, suggesting that the anti-proliferation target(s) of NGF
may be different from that of 5-FU, which is known to inhibit thymidilate
synthase. CONCLUSIONS: This study demonstrates that NGF can enhance the anti-proliferation
effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease
the dosage of 5-FU needed for colorectal cancer treatment.
Wierstra, I. and
J. Alves (2008). "The c-myc promoter: still MysterY and challenge." Adv Cancer
Res 99: 113-333.
The transcription factor c-Myc is a key regulator of cell
proliferation, cell growth, differentiation, and apoptosis. Deregulated c-myc
expression possesses a high transformation potential and the proto-oncogene
c-myc represents a promising target in anticancer therapy. This review on
the c-myc promoter describes its organization, the different levels of its
normal regulation (including initiation and elongation of transcription,
the dual P1/P2 promoters, chromatin structure, c-Myc autosuppression) as
well as its deregulation in Burkitt's lymphoma. Furthermore, it summarizes
the many different transcription factors, signal transduction pathways, and
feedback loops that activate or repress c-myc transcription. Finally, a concept
for regulation of the c-myc promoter in different biological settings, for
example, immediate-early induction, constant expression throughout the cell
cycle in continuously cycling cells, repression during terminal differentiation
and deregulation in cancer, is formulated.
Woerner, S. M., M. Kloor, et al.
(2005). "Microsatellite instability of selective target genes in HNPCC-associated
colon adenomas." Oncogene 24(15): 2525-35.
Microsatellite instability (MSI)
occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less
frequently in sporadic tumors as the result of DNA mismatch repair (MMR)
deficiency. Instability at coding microsatellites (cMS) in specific target
genes causes frameshift mutations and functional inactivation of affected
proteins, thereby providing a selective growth advantage to MMR deficient
cells. At present, little is known about Selective Target Gene frameshift
mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated
MSI-H colorectal adenomas of different grades of dysplasia for frameshift
mutations in 26 cMS-bearing genes, which, according to our previous model,
represent Selective Target genes of MSI. About 30% (8/26) of these genes
showed a high mutation frequency (> or =50%) in colorectal adenomas, similar
to the frequencies reported for colorectal carcinomas. Mutations in one
gene (PTHL3) occurred significantly less frequently in MSI adenomas compared
to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023).
Biallelic inactivation was observed in nine genes, thus emphasizing the
functional impact of cMS instability on MSI tumorigenesis. Some genes showed
a high frequency of frameshift mutations already at early stages of MSI
colorectal tumorigenesis that increased with grade of dysplasia and transition
to carcinoma. These include known Target Genes like BAX and TGFBR2, as
well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have
identified genes of potential relevance for the initiation and progression
of MSI tumorigenesis, thus representing promising candidates for novel
diagnostic and therapeutic approaches directed towards MMR-deficient tumors.
Wrzesinski, S. H., M. L.
McGurk, et al. (2007). "Successful desensitization to oxaliplatin with incorporation
of calcium gluconate and magnesium sulfate." Anticancer Drugs 18(6): 721-4.
Since the results of the MOSAIC trial demonstrated an improved disease-free
survival in stage III colorectal patients treated with oxaliplatin combined
with 5-fluorouracil and folinic acid when they were compared with those treated
with 5-fluorouracil and folinic acid alone, the addition of this organoplatin
to 5-fluorouracil and folinic acid has become first-line adjuvant treatment
for stage III colorectal cancer. Unfortunately, there is a small population
of patients who develop grade III/IV hypersensitivity reactions to oxaliplatin
which, until recently, have interfered with further treatment with oxaliplatin-containing
regimens. Successful oxaliplatin desensitization protocols for patients having
severe oxaliplatin hypersensitivity reactions have been reported. However,
none of these protocols, have incorporated magnesium and calcium salts. Retrospective
data has suggested that pretreating colorectal cancer patients with magnesium
sulfate and calcium gluconate before the administration of oxaliplatin may
reduce the incidence of neurotoxicities induced by this drug. Therefore,
we modified a previously published oxaliplatin-desensitization protocol by
incorporating intravenous calcium gluconate and magnesium sulfate, and report
a patient with stage IIIc colorectal cancer and prior severe hypersensitivity
reactions to oxaliplatin who underwent successful oxaliplatin desensitization
using this protocol.
Wynter, M. P., S. T. Russell, et al. (2004). "Effect
of n-3 fatty acids on the antitumour effects of cytotoxic drugs." In Vivo
18(5): 543-7.
BACKGROUND: n-3 fatty acids are increasingly being administered
to cancer patients for the treatment of cachexia, and it is thus important
to know of any potential interactions with ongoing cytotoxic drug therapy.
MATERIALS AND METHODS: For this reason eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) were administered to mice bearing the cachexia-inducing MAC16
colon adenocarcinoma, and the effect of epothilone, gemcitabine, 5-fluorouracil
and cyclophosphamide on tumour growth and body weight determined. RESULTS:
Epothilone alone had a minimal effect on tumour growth rate, but this was
potentiated by DH4, while for 5-fluorouracil and cyclophosphamide tumour
growth inhibition was enhanced by EPA. The antitumour effect of gemcitabine
was not altered by either fatty acid. EPA arrested the development of cachexia,
while DHA had no effect and the same was true for their effect on tumour
growth rate. The anticachectic effect of EPA was only seen in combination
with 5-fluorouracil. CONCLUSION: These results suggest that n-3 fatty acids
do not interfere with the action of chemotherapy and may potentiate the effect
of certain agents.
Zaman, G. J., J. Lankelma, et al. (1995). "Role of glutathione
in the export of compounds from cells by the multidrug-resistance-associated
protein." Proc Natl Acad Sci U S A 92(17): 7690-4.
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