Antioxidants & Chemotherapy for Advanced Prostate Cancer
THE LATEST RESEARCH ON SPECIFIC INTERACTIONS
INTRODUCTION
It has been commonly assumed that all chemotherapy drugs are incompatible
with all antioxidants, but there is a growing body of evidence that
suggests this might not always be the case (Lamson and Brignall 1999).
While some antioxidants are clearly not beneficial and can even decrease
effectiveness of some chemotherapeutic treatments for certain cancers,
there are many other antioxidants that do not interfere and may even
enhance specific chemotherapy drugs, while also decreasing their side
effects.
For this article, we investigated treatments for advanced metastatic
prostate cancer, for which there are a limited number of chemotherapy
treatments available. Although we focus on metastatic disease, some
of the antioxidants discussed in this article are relevant for men
with localized prostate cancer as well as for those who are at high
risk for developing prostate cancer.
PROSTATE CANCER AND ITS TREATMENT
Prostate cancer is the second most common cancer in men after skin cancer.
The most common form of prostate cancer occurs in men age 65 or older,
and is often a slow growing, localized disease limited to the prostate
gland. For this type of prostate cancer, there are a variety of treatments,
including "watchful waiting," radiation
(including seeds), cryotherapy, surgery, High Intensity Focused Ultrasound
(HIFU), hormone suppressing drugs (Androgen Deprivation Therapy), as
well as other novel treatments. (See Glossary at the end of this article
for brief descriptions of these terms.)
If cancer
of the prostate gland goes untreated or undiagnosed, it can begin to
metastasize, either slowly over many years or, in some cases, very rapidly.
When prostate cancer metastasizes, it can spread locally to the pelvic
bones, bladder, and other nearby organs. Advanced metastatic prostate
cancer commonly progresses to distant sites in the bones but can also
spread to other organs.
The first line of treatment for metastatic prostate cancer is usually
hormone suppression therapy. This is called Androgen Deprivation Therapy
(ADT) and includes drugs such as leuprolide (Lupron), goserelin (Zoladex),
flutamide (Eulexin), bicalutamide (Casodex), nilutamide (Nilandron),
or cyproterone (Androcur, Cyprostat). Secondary hormone therapy may be
used if and when the first treatment does not work. This would include
a combination of the same drugs listed above and may include others as
well.
When Androgen Deprivation Therapy stops working, patients move on to
chemotherapy, starting with drugs such as paclitaxel (Taxol), docetaxel
(Taxotere), or mitoxantrone (Novantrone). Off-label or clinical trial
chemotherapy drugs are sometimes added, such as carboplatin (Paraplatin),
cisplatin (Platinol), satraplatin, epothilone, or doxorubicin (Adriamycin).
Research has shown that chemotherapy has limited potential for controlling
progression of metastatic prostate cancer, leading to the addition
of newer therapies (in combination with chemotherapy or not) and clinical
trials.
Some of the newer therapies, which can be
considered, include: anti-angiogenesis drugs, such as bevacizumab (Avastin)
or sunitinib (Sutent), which stop new blood vessels from growing; immune
therapy, which stimulates the immune system to fight cancer; and gene
therapy, which uses genetic material in the treatment of disease, including
GVAX, ipilimumab (MDX -010), Granulocyte-Macrophage Colony-Stimulating
Factor (GMCSF), and sipuleucel-T (Provenge).
RESEARCH ON HOW ANTIOXIDANTS AND CANCER THERAPIES WORK TOGETHER
As new approaches to treating advanced prostate cancer in conjunction
with chemotherapy are being developed, it becomes more and more useful
to explore approaches that involve increasing the effectiveness of
chemotherapy while decreasing its side effects. There are antioxidants
that, when properly combined with chemotherapy, have been shown to
produce this effect. Although it is not commonly known, these combinations
have been investigated as early as the 1980’s
(Lamson and Brignall 1999) and one published scientific review reported
on the results of over 180 studies specifically investigating antioxidant/chemotherapy
and antioxidant/radiation combinations (Lamson and Brignall 1999).
The following are brief summaries of more recently published evidence
on the combination of antioxidants and chemotherapy specifically for
advanced metastatic prostate cancer:
CURCUMIN
Curcumin is an active component of the Indian curry spice turmeric. Curcumin
is known for its antitumor, antioxidant, anti-amyloid, and anti-inflammatory
properties. It also promotes healthy bile excretion and healthy platelet
function.
Curcumin & Chemotherapy
Curcumin appears to block a protein that plays a role in the resistance
to the chemotherapy drug mitoxantrone. It therefore may be compatible
with mitoxantrone (Chearwae, Shukla et al. 2006). However, curcumin
appears to block a pathway by which taxol based drugs (taxanes) cause
tumor suppression and therefore should not be taken in combination
with taxanes (Wang and Wieder 2004).
MELATONIN
Melatonin is a hormone released from the pineal gland and helps to improve
quality of sleep. It is also known to reduce metastasis in cancer patients.
Melatonin & Chemotherapy
Melatonin’s antioxidant activity appears to counteract toxicity
of common chemotherapy treatments for advanced prostate cancer, including
cisplatin, mitoxantrone, and paclitaxel. Melatonin significantly reduces
the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis,
and asthenia related to chemotherapy. Additionally, melatonin promotes
cancer cell death when combined with the same therapies (Lissoni, Barni
et al. 1999). In a human clinical trial, melatonin at a dosage of 20mg
combined with intra-muscular hormone therapy triptorelin (Trelstar, Depot,
Trelstar LA) decreased levels of prostate specific antigen (PSA) and
growth factors for metastatic prostate cancer (Lissoni, Cazzaniga et
al. 1997).
GENISTEIN
Genistein is a soy extract that may help cancer prevention. It also inhibits
proliferation of invasive prostate cancer.
Genistein & Chemotherapy
Genistein significantly improves the antitumor activity of docetaxel,
doxorubicin, and cisplatin through several different mechanisms. Genistein,
when used alone, also has anticancer activity without toxicity (Li,
Ahmed et al. 2005; Li, Kucuk et al. 2006).
EPIGALLOCATECHIN-GALLATE
(EGCG)
Epigallocatechin-gallate (EGCG) is one of the components of green tea
extract, which is made from the dried leaves of an Asian evergreen shrub.
EGCG is 25 to 100 times more potent an antioxidant than vitamin C. Research
studies have found that in men who are at high risk for prostate cancer,
EGCG reduces the incidence of those men developing the disease.
EGCG & Chemotherapy
An in vitro study found that when EGCG is used in combination with paclitaxel,
hormone refractory prostate cancer cells developed resistance to treatment
sooner than either paclitaxel or EGCG alone (Axanova, Morre et al.
2005).
CAPSAICIN
Capsaicin is a chili pepper extract, often topically used to reduce pain
and inflammation. It is also used for anticancer treatment.
Capsaicin & Chemotherapy
An in vitro study showed that when capsaicin is used in combination with
paclitaxel, hormone refractory prostate cancer cells developed resistance
to treatment. When used in combination with cisplatin, it reduces the
effectiveness of the cisplatin (Axanova, Morre et al. 2005).
CAPSIBIOL-T
Capsibiol-T is a combination of EGCG and capsaicin.
Capsibiol-T & Chemotherapy
In vitro studies show that when hormone refractory prostate cancer cells
are pretreated with Capsibiol-T and then treated with paclitaxel, the
combination has an additive effect in decreasing survival of cancer
cells (Axanova, Morre et al. 2005).
VITAMIN D3
Vitamin D3 is metabolized into calcitriol. In one trial, researchers
used a formulation of calcitriol called DN 101 that does not have as
many problems with toxicity as vitamin D3 when used at high doses.
High doses of calcitriol alone appear to inhibit hormone refractory
metastatic prostate cancer cell growth and stimulate cancer cell death,
as well as inhibit the invasiveness of prostate cancer cells (Schwartz,
Wang et al. 1997). It has also been shown to increase differentiation
of prostate cancer cells (Esquenet, Swinnen et al. 1996; Bauer, Thompson
et al. 2003).
Vitamin D3 & Chemotherapy
In combination with docetaxel, vitamin D3 has an additive effect. In
a recent study, docetaxel used with a specific formulation of calcitriol
(DN 101) increased survival rate in hormone refractory metastatic prostate
cancer patients (Beer, Ryan et al. 2007).
VITAMIN
A
Vitamin A is an essential nutrient for humans and has many diverse functions
in maintaining normal health. It has various different metabolites that
are similar in structure and, with a few changes, can become vitamin
A with the help of enzymes in the body.
Vitamin A & Chemotherapy
Retinoic Acid (an acidified form of vitamin A) has a synergistic effect
in combination with docetaxel through two known
mechanisms therefore increasing docetaxel’s ability to stop tumor
growth (Sun, Li et al. 2004).
13-cis-retinoic acid (a vitamin A derivative) has
been shown in in-vitro trials in combination with paclitaxel to have
a synergistic effect in inhibiting the growth of prostate cancer cell
lines (it enhances the effectiveness of paclitaxel in attacking cancer
cells). However, in combination with carboplatin, it has an antagonistic
effect (it diminishes effectiveness of carboplatin) (Cabrespine, Bay
et al. 2005).
All-trans retinoic acid (a vitamin A derivative) helps Taxol-based
drugs (taxanes) to increase cancer cell death (Wang and Wieder 2004).
SILIBININ
Silibinin is an extract from milk thistle seed that is known for its
ability to protect the liver.
Silibinin & Chemotherapy
Silibinin and platinum-based compounds (cisplatin, carboplatin, satraplatin),
when used together, have a substantially higher ability to inhibit
prostate cancer cell growth and cause prostate cancer cell death, when
compared with platinum-based compounds alone (Dhanalakshmi, Agarwal
et al. 2003).
BETA-GLUCAN
Beta-glucans are natural soluble fiber polysaccharides found in the bran
of cereal grains such as barley, oats, rye, and wheat. Beta-glucans
can also be extracted from maitake mushrooms, as in the following study.
Maitake Beta-glucan & Chemotherapy
In combination with carmustine (BCNU), maitake beta-glucan enhances
effectiveness of chemotherapy, with a 90% cancer cell viability reduction
(Finkelstein, Aynehchi et al. 2002).
WHAT IF THERE IS INSUFFICIENT EVIDENCE FOR INTERACTIONS BETWEEN SPECIFIC
CHEMOTHERAPY DRUGS AND SPECIFIC ANTIOXIDANTS?
When it is uncertain whether a specific antioxidant and chemotherapy
drug treatment combination would conflict, then the possibility of combining
them largely depends on the timing of their use. It is important to know
that most water-soluble antioxidants usually stay in the blood for one
day or less while oil-soluble antioxidants can stay in the blood for
up to several days. This information, in combination with the known half-life
of chemotherapy drugs (which is generally 72 hours or less), can allow
patients and health care providers, working together in a process of
shared decision-making, to make an informed decision on whether or not
to combine certain antioxidants within the same treatment protocol. If
a decision is made to use antioxidants intermittently, some healthcare
providers will choose to separate their use by at least three days to
allow time for chemotherapy drugs to complete their intended purpose
before being metabolized.
CONCLUSION
Although this article only briefly touches on the possibility of combining
some antioxidants with chemotherapy as an effective way for treating
cancer, our hope is that it encourages both patients and health care
providers to more seriously consider the importance of these various
combinations. One must, of course, be judicial in determining which combinations
are safe, but when the cancer research community is constantly looking
for ways to make cancer treatments more effective and to help people
live longer, antioxidant-chemotherapy combinations are worthy of further
study and deeper understanding.
Special thanks to Johanna Altgelt and Jeremy Paster for their significant
contributions to this article.
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GLOSSARY OF TERMS
Androgen Deprivation Therapy: Medications that work
by decreasing the amount of testosterone.
Bevacizumab (Avastin): A synthetic antibody often used
along with chemotherapy, first developed to treat colon and rectal cancer
that has spread to other parts of the body. It works by blocking a protein
called vascular endothelial growth factor (VEGF), which decreases the
blood supply to the tumor.
Bicalutamide (Casodex): A drug used in combination with
hormone treatment to treat prostate cancer that has spread to other areas
of the body. It works by blocking the action of testosterone in the prostate.
Carboplatin (Paraplatin): A platinum-containing anticancer
drug that is an analog of cisplatin with somewhat reduced toxicity and
that is used in the treatment of various cancers.
Chemotherapy: The use of chemical agents in the treatment
or control of disease, especially cancer.
Cisplatin (Platinol): A platinum-containing anticancer
drug that functions by producing cross links in DNA between and within
strands.
Cryotherapy: The therapeutic use of cold, such as in cryosurgery.
Cyproterone: A synthetic steroid used in the form of
its acetate to inhibit androgenic secretions (as testosterone).
Docetaxel (Taxotere): A semisynthetic antineoplastic
drug derived from the needles of the yew tree.
Doxorubicin (Adriamycin): An anthracycline antibiotic
with broad antineoplastic activity that is obtained from a bacterium
of the genus Streptomyces (S. peucetius) and is administered in the form
of its hydrochloride.
Epothilone (Ixabepilone): A new type of drug with the
same mechanism as the taxanes, which may have greater potency than paclitaxel,
have activity in tumors that are resistant to paclitaxel, can stay in
cancer cells longer, and can be useful in people who have already had
several different types of aggressive therapies.
Excretion: The act or process of separating or eliminating
substances from the body.
Flutamide: A nonsteroidal antiandrogen that is used
in the treatment of prostate cancer.
Goserelin (Zoladex): A drug that is similar to luteinizing
hormone releasing hormone (LHRH), which is made by the body. It decreases
the hormone testosterone, which can help slow or stop the growth of prostate
cancer cells.
Granulocyte-Macrophage Colony-Stimulating Factor
(GM-CSF): A hormone essential in augmenting the body’s
immune response to vaccines.
GVA X: An immunotherapy for prostate cancer, made from
two genetically-modified prostate cancer cell lines, currently in clinical
trials for advanced-stage prostate cancer.
Half-life: The time required for half the amount of
a substance (as a drug or radioactive tracer) in or introduced into a
living system or ecosystem to be eliminated or disintegrated by natural
processes.
High Intensity Focused Ultrasound (HIFU): The therapeutic
use of ultrasound that is much more powerful and focused than ordinary
diagnostic ultrasound.
Interaction: The effect of one drug, food, or vitamin
on the effectiveness or metabolism of another drug. This can be synergistic,
in which the effect of the drug is increased, or antagonistic, in which
the effect of the drug is decreased or blocked.
Leuprolide (Lupron): A synthetic analog of gonadotropin-releasing
hormone used to treat cancer of the prostate gland. It works by reducing
the amount of testosterone that the body makes. This can help slow or
stop the growth of prostate cancer cells and helps relieve symptoms like
painful or difficult urination.
Metabolism: The sum of the processes by which a particular
substance is handled (as by assimilation and incorporation or by detoxification
and excretion) in the living body.
Metastatic: Having to do with the transfer of cancer
from one part of the body to another..
Mitoxantrone: An antineoplastic drug that is used in
the form of its dihydrochloride either alone or in combination in the
treatment of some leukemias and carcinomas.
Nilutamide (Nilandron): A drug used in combination with
surgery or other medications to treat prostate cancer. Testosterone,
a natural hormone in men, stimulates the growth of prostate cancer cells.
Nilutamide is an anti-androgen that works by blocking the effects of
testosterone.
Provenge: A new vaccine currently in clinical trials
for advanced stage prostate cancer.
Radiation: Energy radiated in the form of waves or particles
used, for example, in medicine to stop the growth of cancer cells.
Sunitinib (Sutent): A newly developed drug, which works
by decreasing the blood supply to tumor cells.
Taxanes: A group of drugs that includes paclitaxel (Taxol)
and docetaxel (Taxotere), which are used in the treatment of cancer.
Taxanes have a unique way of preventing the growth of cancer cells: they
affect cell structures called microtubules, which play an important role
in cell functions. In normal cell growth, microtubules are formed when
a cell starts dividing. Once the cell stops dividing, the microtubules
are broken down or destroyed. Taxanes stop the microtubules from breaking
down; cancer cells become so clogged with microtubules that they cannot
grow and divide.
Watchful Waiting: An approach by which patients are
given no immediate treatment until the tumor shows signs of progressing,
often offered to men diagnosed with early stage prostate cancer. Less
often recommended following recent publication of a study showing better
10-year survival rates in men who received either surgery or radiation
therapy, compared to those who elected for watchful waiting approach.
(Tewari, A., G. Divine, et al. 2007)
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