(Print Version) Prostate Cancer: Adjuvant Therapy

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. Dr. Strum and his partner, Mark C. Scholz, M.D., have a medical practice (Healing Touch Oncology) in Marina del Rey, California, that cares for patients with prostate cancer (PC) or who are at high risk of having PC.

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 Mega Soy Extract. Each 700-mg capsule of Mega Soy 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), pamidro-nate (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

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 anti-angiogenesis 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:

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THIS INFORMATION (AND ANY ACCOMPANYING PRINTED MATERIAL) IS NOT INTENDED TO REPLACE THE ATTENTION OR ADVICE OF A PHYSICIAN OR OTHER HEALTH CARE PROFESSIONAL. ANYONE WHO WISHES TO EMBARK ON ANY DIETARY, DRUG, EXERCISE, OR OTHER LIFESTYLE CHANGE INTENDED TO PREVENT OR TREAT A SPECIFIC DISEASE OR CONDITION SHOULD FIRST CONSULT WITH AND SEEK CLEARANCE FROM A QUALIFIED HEALTH CARE PROFESSIONAL.

epicatechin (EC)

epigallocatechin (EGC)
epicatechin gallate (ECG)

epigallocatechin gallate (EGCG)

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 intra-peritoneal 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.

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.

Recent studies have shown a statistically significant inverse relationship between the ingestion of tomatoes, tomato sauce, and pizza with the development of prostate cancer. In a 6-year study by Giovannucci et al. (J. Natl. Cancer. Inst., 1995) involving the intake of carotenoids and retinol in 47,894 men, lycopene-rich foods significantly lowered the risk of PC. Men who ingested 10 or more servings of tomatoes in several forms (sauce, juice, raw, or on pizza) had a 41% reduction in PC, while those who ate four to seven servings a week had a 22% reduction. Tomatoes and tomato sauce contain high amounts of lycopene, a carotenoid. Lycopene is the most predominant carotenoid in plasma and in various tissues, including the prostate gland. Lycopene is the most efficient scavenger of singlet oxygen among the common carotenoids. Lycopene is not converted to vitamin A. The major contributors to the specific carotenoids are shown below:

Carotenoid Class	Vegetable or Fruit
?-carotene	Carrots, yams, sweet potatoes, spinach
?-carotene	Carrots, mixed vegetables
Lutein	Spinach, broccoli, kale, mustard, chard
Lycopene	Tomatoes, tomato sauce, pizza, tomato juice
?-cryptoxanthin	Oranges

Another study evaluated the effect of lycopene on the development of mammary cancers in a mouse model. This showed a significant suppression of tumor growth in those mice receiving a diet supplemented with lycopene. Decreases in thymidylate synthetase within the breast tissue, lower levels of serum-free fatty acids, and decreased plasma prolactin levels by the pituitary were characteristic of the lycopene-supplemented group (Nagasawa et al., Anticancer Res., 1995). Interestingly, the source of lycopene was a beta-carotene-rich algae called Dunaliella bardawil.

Recently, Kucuk et al. reported on 30 men with localized PC scheduled for radical prostatectomy. They were randomly assigned to receive either 15 mg of lycopene (Lyc-o-Mato, LycoRed, Beer Sheva, or Israel) orally twice daily, or no intervention for 3 weeks prior to surgery. Prostate specimens were step-sectioned, entirely embedded, and evaluated for pathological stage, Gleason score, the volume of PC, as well as the extent of PIN (a pathological finding often associated with PC) in the gland. The specimens were also examined for biomarkers of cell proliferation, differentiation, and apoptosis. Comparisons were made between intervention and control groups. Serum and tissue lycopene levels increased by 22% in the intervention group. At RP, within the treated group, 8 of 12 patients (67%) had organ-confined PC, and 84% had tumors < 4 cc, compared to 44% and 55%, respectively, in the control group. Lesser glandular involvement by PIN was also observed in the intervention group. The expression of biomarkers of proliferation decreased, whereas the markers of differentiation and apoptosis increased in the intervention group. Serum PSA level also decreased significantly in the intervention group but not in the control group. The results suggest a role for lycopene in PC prevention. This is a very exciting study, and the full report should be published shortly. We currently advise patients with active PC to include 30 mg a day of lycopene in their diet.

Restrict Total Caloric Intake to 500 Calories a Meal

We believe that diet should be regarded as having serious biochemical relevance to the health of the individual. You are, for the most part, what you eat. Western society, and especially the United States, are over-consumers of calories. Excessive caloric consumption is a significant factor that adversely effects longevity. Caloric restriction has been shown to be an important factor in augmenting the immune system and improving longevity. We need to rethink how much food we need to eat. Our ideal body weight should be taken seriously. If we were to do this alone, we would virtually eliminate diabetes, hypertension, hypercholesterolemia, stroke, heart disease, and a significant amount of cancer from our lives. Patients should strive at a general figure of 500 calories a meal, and 100 calories per snack. Modifications of this are based on the level of activity, age, and body surface area. Nutritional software or nutritional counseling should be an integral part of our approach to good health.

Eliminate Smoking, Reduce Alcohol Consumption,
and Exercise Properly

Avoid Excessive Carbohydrate Intake to Prevent Hyperinsulinemia and the Generation of Unfavorable Eicosanoids

The dietary fat issue is significant. There are studies that show dietary fat to increase the growth rate of PC in animal models of human PC. However, the emphasis on dietary fat per se has taken attention away from caloric over-consumption. Fat excess, however, is linked to excessive calorie consumption, since fat contains twice as many calories, gram for gram, as protein or carbohydrate. In addition, the ratio of protein to carbohydrate in our meals is related to how our body reacts to the intake of food and how it handles calories that are ingested. The reader is advised to read Barry Sears's book The Zone, 1995, and Anti-Aging Zone, 1999, for an in-depth discussion of the dangers of over-consumption of carbohydrates and the ill effects of hyperinsulinemia that occur as a result. Our patients are advised to incorporate Sears's approach into their lives while consuming fewer calories a day and exercising moderately. The value of generating favorable eicosanoids is discussed in detail in both of these books. The free radical-generating fatty acid called arachidonic acid, an unfavorable eicosanoid, has been shown to stimulate PC cell growth. The molecular pathway of arachidonic stimulation involves the inflammatory enzyme 5-lipooxygenase. Recent papers show that inhibition of arachidonic acid leads to PC programmed cell death, or apoptosis (Ghosh and Myers, Proc. Natl. Acad. Sci. USA, 1998). Lipooxygenase also is involved in the formation of abnormal blood clots. Nutrients that specifically inhibit 5-lipooxygenase include garlic. Fish oil supplements (EPA), an omega-3 fatty acid, have been shown to suppress arachidonic acid formation.

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclooxygenase. A particularly dangerous prostaglandin is PGE2, which is involved in many chronic inflammatory diseases. The administration of PGE2 to prostate, breast, and colon-cancer cells resulted in increased cellular proliferation. An ibuprofen derivative called Flurbiprofen inhibited PGE2-induced PC cell growth (Tjandrawinata et al., Br. J. Cancer, 1997). Aspirin, ibuprofen, and fish oil are other available agents that inhibit PGE2 synthesis. The eicosanoid pathways are shown in Figure 2 on the following page.

Use Free-Radical Scavengers (Selenium and Vitamin E)
to Prevent Oxidative Damage

In conjunction with dietary restriction of calories and alteration in the nature of the calories consumed as well as moderating our exercise, there is evidence that aging, degenerative disease, and cancer are all expressions of varying degrees of cellular oxidative damage. In fact, fat itself induces the generation of fatty acid peroxides that generate damaging free radicals. The concept here is that living organisms are subject to oxidation just as metal is subject to rusting. As part of aging, we see the sequelae of such oxidation manifested in the graying of hair, short-term memory loss, cataract formation, gum and jaw recession, vascular disease, cardiac disease, degenerative joint disease, and sun-induced skin changes ranging from wrinkling to skin cancer. The majority of items in health food stores today are antioxidants. In regards to PC, there are now studies that show that vitamin E and selenium use will decrease the incidence as well as the mortality from PC. The ATBC study by Heinonen et al. (J. Natl. Cancer Inst., 1998) demonstrated a 32% decrease in the incidence of PC and a 41% lower mortality rate from PC in men taking alpha-tocopherol (vitamin E). Another study by Fleshner et al. (J. Urol., 1998) showed a reduction in growth rates of transplanted LNCaP cells in athymic mice induced by a high-fat diet (40.5%) by dl-alpha tocopherol (synthetic vitamin E). The landmark study by Clark et al. (JAMA, 1996) provided evidence that 200 mcg of selenium could reduce the incidence of PC by 63%. This is consistent with the observation that selenium inhibited the growth of DU-145--an androgen-independent human cell line of PC--by 50% at a selenium dose of 1 × 10-6 M and by 98% at a dose of 10-4 M. For comparison, selenium serum levels in humans living in high-selenium areas may be as high as 10-6 M (Webber et al., Biochem. Biophys. Res. Commun., 1985). Our recommended vitamin E dose for prevention is 400 to 1000 IU a day as mixed tocopherols. Mixed tocopherols contain synthetic vitamin E (d-alpha- tocopherol and dl-alpha-tocopherol) as well as natural vitamin E. A study by Moyad et al. (in press, 1999) indicates gamma tocopherol has more anti-PC activity then conventional d-alpha-tocopherol.

The selenium dose recommended for prevention is 400 mcg a day. This is best given as selenomethionine, usually derived from yeast. Selenium works best in conjunction with vitamin E, which enhances its activity. Vitamin E works best in association with beta-carotene and vitamin C. We recommend 1000 mg of vitamin C to be taken after each meal to prevent fatty acid peroxide generation. In a likewise manner, Coenzyme Q10 has been shown to prevent the oxidation of LDL cholesterol. In fact, the prevention of fatty acid oxidation may be just as important as decreasing fat consumption. We suggest Coenzyme Q10 be taken at a dose of 200 mg a day. An added benefit of CoQ10 is the improvement in heart function and diabetic control as well as the treatment of periodontal disease. CoQ10 works best when given with vitamins
E and C.

Use Genistein to Decrease Cell Adhesion, Slow Proliferation,
and Decrease Metastatic Potential

Incidences of PC are higher in the Western world than in Asia, where soy is consumed as part of the normal diet, producing higher levels of genistein in the blood, which in turn appear to prevent the expression of metastatic capacity in hormone-dependent cancers. Studies have shown that, in a cell-culture system, genistein appears to be cytotoxic and inhibitory of PC cell proliferation (Santibanez et al., Anticancer Res., 1997; Peterson and Barnes, Prostate, 1993). Genistein's protein-tyrosine kinase-inhibiting effects have been identified as a cancer-prevention mechanism. One study examined genistein's effect upon cell adhesion as one possible mechanism by which it could be acting as an antimetastatic agent. A morphogenic analysis revealed that genistein caused cell flattening in a way that prevented metastatic adhesion of PC cell lines. We advise patients to eat a diet rich in soy products such as tofu, soy beans (edamame), soy milk, and miso. We recommend a breakfast and dinner drink that contains soy milk, isolated soy powder, many of the vitamins mentioned above, and strawberries. We use a Vita-Mix blender to pulverize the vitamins and add them to this drink. The protein-to-carbohydrate ratio of this drink is also close to the desired 3:4 ratio that Sears considers "zone" favorable. Life Extension makes a 700-mg Mega Soy product that contains 134 mg of genistein per capsule as well as the isoflavones daidzein, and glycitein. We would suggest that clinical trials be initiated that would determine the genistein oral intake associated with blood genistein levels similar to those found in Asian men. Currently, we recommend 100 to 200 mg of genistein a day in addition to a diet high in soy products. We also believe that the major source of protein in our diet should come from soy.

Decrease Cell Proliferation with Pygeum and Silymarin

Pygeum extract also has been shown to specifically inhibit prostate-cell proliferation by inhibiting protein kinase C enzyme activity (Yablonsky et al., J. Urol., 1993). Silymarin has been shown to have an anti-PC effect by virtue of increasing the levels of p27 (Zi et al., Cancer Res., 1998; Gali et al., Proc. Annu. Meet. Am. Assoc. Cancer Res., 1994). Silymarin also has protective effects against liver cell injury and skin cancer (Kropacova et al., Radiat. Biol. Radioecol., 1998; Agarwal et al., Proc. Annu. Meet. Am. Assoc. Cancer Res., 1995; Katiyar et al., J. Natl. Cancer Inst., 1997).

Product availability: Mega Soy Extract, lycopene, silymarin, pygeum/saw palmetto extract, selenium and vitamin E can be ordered by phoning 1-800-544-4440 or order OnLine Lycopene