Prostate Cancer (Adjuvant Therapy): Online Reference For Health Concerns

Dr. Strum is on the Life Extension Medical Advisory Board, and Dr. McDermed is from the Prostate Cancer Research Institute (PCRI) in Los Angeles, California. Drs. Strum and McDermed are proponents of a holistic medical strategy that combines peer-reviewed conventional scientific publications with new findings in the areas of nutrition and supportive care of the patient.

We have routinely employed natural therapies in our holistic approach to oncology and internal medicine disorders for almost 30 years. Such therapies are based on published peer-reviewed literature and not hearsay from individuals or companies that appear to be in the business of medicine. The amount of literature in this area has grown exponentially. We are now at a phase in our acceptance of such approaches that medical studies are being conducted to verify the benefits of such "nutriceuticals" in pilot clinical trials with endpoints that are objectively evaluable. Most of the recommendations in this section are directed to one or more phases of prostate cancer (PC) management: prevention, early-stage treatment, late-stage treatment, and/or maintenance phase of active treatment. During radiation therapy, there is concern that the use of high doses of antioxidants will protect tumor cells from the cell-killing effects of radiation. This is a controversial issue. There is a randomized study indicating significant reduction in the radiation-induced side effects of cystitis and proctitis using SOD (Orgotein) in patients receiving radiation therapy (RT) for bladder cancer. This study involved 448 patients. It showed a dramatic lessening in the radiation therapy-induced side effects in the SOD treated arm (Sanchiz et al., Anticancer Res., 1996). The differences in anticancer results in the treatment arm receiving Orgotein versus placebo are still not known. Orgotein is an injectable SOD drug approved in Europe, but not in the United States.

We use the nutritional approaches during the preventive phase in men at risk for developing PC. We employ the same strategy during the initial use of androgen deprivation therapy (ADT) and during the off-phase of ADT for the purpose of slowing the growth rate of PC as much as possible. In patients with active PC, we take a more aggressive stance on the dosing of these agents and also suggest the use of additional agents that appear promising in their activity against PC. However, it is important to indicate that the rationale for the use of many of these adjuncts is based on studies involving human cell lines of PC grown in animal models, usually mice. Clinical studies in humans have either not been started or are in progress but are too preliminary to report at this time.

As noted above, we suggest the use of selenomethionine derived from yeast. We have seen no selenium toxicity at doses as high as 800 mcg a day. Larry Clark, at the University of Arizona, has recently initiated clinical trials using 800, 1600, and 3000 mcg a day of selenium in patients involved in watchful waiting. At 800 mcg a day, physician monitoring and consideration of selenium blood levels is advised. Please note that selenium blood levels will be elevated in most patients taking any selenium supplementation due to the fact that normal selenium levels were based on population sampling from men and women not taking selenium supplements. If selenium toxicity occurs, the most common signs are abnormalities in nail growth with loss of nails, hair loss, lack of appetite with weight loss, and a garlic-like odor to the breath. Personally, I have only seen hair loss, anorexia, and weight loss in one patient who received a dose of 300,000 mcg of selenium a day. That patient had a drop in his PSA and has had a slow recovery of PSA; he has been off therapy after ADT for 7 years. Carefully controlled trials with selenium such as at the University of Arizona are critically important to our understanding of how best to use selenium. We urge patients doing watchful waiting to join in such trials if this is possible. Call Trish Wilkens or Jennifer Hart at (520) 321-7798 (extension 19 or 23) for further information on this clinical trial.

The use of soy and genistein in the prevention of PC was discussed above. Genistein has been proposed as an effective agent to prevent the expression of metastatic capacity in hormone dependent cancers. In a cell-culture system, genistein appeared to be cytotoxic and inhibitory of PC cell proliferation (Geller et al., Prostate, 1998). Genistein and soy products therefore play a potential major role in established PC. Cancer cells use the enzyme tyrosine kinase as a growth factor. Soy genistein is a potent inhibitor of tyrosine kinase activity. The effects of protein kinase inhibitors on human prostate cell growth have been extensively investigated. Other biological activities of genistein have been demonstrated in animal models and include the following:

In active PC patients, we are exploring higher doses of genistein using Life Extension UltraSoy Extract. Each 700 mg capsule of UltraSoy Extract contains 134 mg of genistein, 122 mg of daidzein, and 24 mg of glycetein. Currently, we are advising two of these capsules a day and are trying to arrange for serum genistein levels.

Other adjunctive therapies known to have an effect on PC include the use of vitamin D. Published studies using more potent synthetic vitamin D analogs such as Rocaltrol or Calcitriol have shown a slowing effect on PC growth (Gross et al., J. Urol., 1998). These analogs affect the p27Kip1 oncogene that results in over-expression of enzymes that inhibit part of the tumor cell cycle (Koike et al., Proc. Annu. Meet. Am. Assoc. Cancer Res., 1997). In short, synthetic vitamin D analogs cause a G1 arrest in the cell cycle by over-expression of cyclin-dependent kinase inhibitors (CDKIs). We routinely use 0.5 mcg of Rocaltrol at bedtime. Rocaltrol requires a physician's prescription. When we employ Rocaltrol, we do so in a comprehensive setting of improving bone integrity. As mentioned earlier, the use of ADT results in an increase in bone resorption due to activation of bone-resorbing cells called osteoclasts. Excessive bone resorption leads to release of bone-derived growth factors that have been shown to play an important role in increasing PC growth. We block this bone resorption by using drugs in the bisphosphonate family. Examples of such drugs currently in use include alendronate (Fosamax), pamidronate (Aredia), and most recently Risedronate (Actonel). The proper use of these agents necessitates physician supervision. As bisphosphonates block excessive bone resorption, they favor bone growth that allows for calcium utilization. Therefore, we routinely combine calcium supplementation when employing bisphosphonate use. We enhance calcium absorption with Rocaltrol or Calcitriol and at the same time get a second benefit from these agents due to their effect on slowing the growth rate of PC cells. Our bone integrity approach therefore involves

2. Calcium citrate. 500 mg with dinner and 500 mg at bedtime. Calcium citrate is much better absorbed than calcium carbonate. Utilization of calcium at night will lower excessive bone resorption by 20%. Calcium intake during the day has no such effect (Blomsohn et al., J. Clin. Endocrinol. Metab., 1994).

3. Synthetic vitamin D (1, 25-dihydroxycho-lecalciferol) as Rocaltrol. 0.5 mcg at bedtime. The use of synthetic vitamin D at bedtime lowers the urinary calcium excretion. This suggests enhanced utilization of calcium and also diminishes the risk of calcium-based kidney stone formation. We are not concerned about the additional use of low doses of ordinary vitamin D (D3) that is commonly added to most of the available calcium citrate products. However, we do recommend monitoring of the serum calcium levels to make sure that calcium balance is appropriate. In addition, the use of magnesium at a dose of at least half the daily intake of calcium will decrease the formation of calcium oxalate stones.

4. Exercise. We do encourage the use of exercise to decrease excessive bone resorption. This should be in the form of both aerobic and muscle-building exercises. We recommend reading Ken Cooper's Anti-Oxidant Revolution as well as Barry Sears's Anti-Aging Zone for detailed exercise programs and other important information.

Antimetastatic Agents

The inhibition of new blood vessel formation to block the growth and spread of PC is currently under investigation. Androgen deprivation therapy (ADT) is known to have this antiangiogenesis effect as well as genistein. Other agents that have an effect on cancer cell invasiveness include green tea polyphenols. Green and black tea are derived from the same plant, Camellia sinensis. However, only green tea is rich in the flavonol group of polyphenols known as catechins. The fermentation process used in making black tea destroys the biologically active polyphenols of the fresh leaf. The catechins as a group have significant free radical scavenging ability and are potent antioxidants. Four catechins are found in green tea leaves:

Of these four factions EGCG is the most important to the PC patient. Pharmacological activity extends beyond its actions as an antioxidant and free radical scavenger. Epigallocatechin-3 gallate (EGCG) acts against urokinase, an enzyme often found in large amounts in human cancers (Jankun et al., Nature, 1997). Urokinase breaks down the basement membrane of cell junctions, which may be a key step in the process of tumor cell metastasis, as well as tumor growth (Ennis et al., Proc. Annu. Meet. Am. Assoc. Cancer Res., 1997). EGCG attaches to urokinase and prevents these actions.

GTP also inhibits ornithine decarboxylase (ODC), resulting in a decrease in polyamine synthesis and cell growth (Carlin et al., J. Urol., 1996). Inhibitors of 5-alpha-reductase (5AR) may be effective in the treatment of 5-alpha-dihydrotestosterone-dependent abnormalities, such as benign prostate hyperplasia, PC, and certain skin diseases. The green tea catechins are potent inhibitors of type-1 but not type-2 5AR (Liao and Hiipakka, Biochem. Biophys. Res. Commun., 1995). They also inhibit accessory sex gland growth in rats. These results suggest the certain tea gallates can regulate androgen action in target organs. The 5AR inhibitor Proscar is predominantly a type-2 inhibitor.

Long-term consumption of tea catechins is common in China and Japan. The frequency of the latent, localized type of PC does not vary significantly between Eastern and Western cultures, but the clinical incidence of metastatic PC is generally lower in Japan and other Asian countries, in contrast to the common occurrence of metastatic PC in Europe and the United States. One possible explanation is that EGCG consumption in green tea in Asian countries prevents the progression and metastasis of PC cells. This explains the lower mortality rate due to PC and breast cancer in Asian countries as compared to Western countries.

In a study investigating the effect of intraperitoneal injections of different catechins on the growth of the human PC cell lines PC-3 and LnCaP, and the human breast cancer cell line MCF-7 grown in nude mice, EGCG was found to play a key role (Figure 1). The injection of EGCG slowed the growth of tumors when administered to the control mice on day 14, while the growth of tumors accelerated when EGCG was stopped in the PC-3 line on day 14. Inhibition of PC-3 growth was EGCG specific; it was not seen with EC, EGC, or ECG (Liao et al., Cancer Lett., 1995). The galloyl group of EGCG appears to be necessary for tumor growth inhibition since EGC is not active. EGCG accounts for about 50% of the solid matter in the hot water extract of green tea that is consumed as a beverage.

Figure 1:EGCG Effect on PC-3 Growth

Green tea is prepared from lightly steamed and dried leaves of the tea plant. The steaming process leaves the polyphenol activity intact. The polyphenol activity varies with climate, season, horticultural practices, and the position of the leaf on the harvested shoot. The Life Extension Foundation makes a 95% green tea extract that contains a high level of the active polyphenol EGCG. The polyphenolic profile of Green Tea 95% Extract is EGCG 35%. Each 350 mg capsule is an extract of green tea leaves containing 122.5 mg of EGCG. One 350 mg capsule of Green Tea 95% Extract is equivalent to 4 to 10 cups of Japanese green tea. Green Tea 95% Extract is available in decaffeinated form, or in a lightly caffeinated extract that contains 10 to 20 mg of caffeine. We suggest that GT 95% be used at a dose of 1 capsule 3 times a day in patients with active PC and perhaps once a day as prevention against PC. We would suggest that GT be taken with food to avoid stomach upset. GT should be kept in a dry, cool location and out of direct light.

Continuation of PROSTATE CANCER: ADJUVANT THERAPY

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