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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