Nutritional Recommendations for Active Prostate Cancer

Reprinted from PCRI Insights July, 1999 vol. 2, no. 3
by Stephen B Strum, M.D.

We employ the same strategy as for Prostate Cancer prevention during the initial use of Androgen Deprivation Therapy 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 too preliminary to report at this time.

Selenium
As noted previously, we suggest the use of selenomethionine derived from yeast. We have seen no selenium toxicity at doses as high as 800 mcg per day. Larry Clark at the U of Arizona has recently initiated clinical trials using 800, 1600 and 3,000 mcg per day of selenium in patients involved in watchful waiting. At 800 mcg per day, we advise physician monitoring and consideration of selenium blood levels. 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, 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 per day. Anecdotally, that patient had a drop in his PSA and has had a slow recovery of PSA; he has been off therapy after ADT for 79 months. 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 Dr. Clark’s trials.

Genestein
The use of soy and genistein in the prevention of PC was also discussed in the previous article. 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.1 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. The biologic activities of genistein that have been demonstrated in animal models include:

• Inhibition of DNA topoisomerase (class of enzyme)
   
• Inhibition of protein tyrosine kinase
   
• Anti-angiogenesis by modulation of FGF (fibroblast growth factor)
   
• Inhibition of EGF (epidermal growth factor)

In active PC patients, we are exploring higher doses of genistein using Life Extension’s 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 genestein levels.

Synthetic Vitamin D, Bisphosphonates, Calcium Citrate
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.2 These analogs effect the p27Kip1 oncogene that results in over-expression of enzymes that inhibit part of the tumor cell cycle.3 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:

1. Synthetic Vitamin D

• Synthetic vitamin D (1,25 dihydroxycholecalciferol) 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.

2. Bisphosphonate Compounds

• Actonel® – 30 mg one hour before breakfast taken with water or
   
• Fosamax® – 10 mg one hour before breakfast taken with water and/or
   
• Aredia® – 30 mg intravenous first dose over 1.5 hours followed every two weeks by 60-90 mg over 1.5 hours.

Patients unable to tolerate Fosamax®, or those whose insurance does not allow them to qualify for Aredia® (bone metastases are currently an insurance requirement), may use Miacalcin® nasal spray once a day to decrease bone resorption and enhance bone formation. Patients with severe bone resorption who are not responding to just one of these agents may require the combination of two anti-osteoclastic agents. We monitor the effectiveness of the above therapies with the Pyrilinks-D™ urine test to quantitate bone resorption. Bone mineral density (BMD) evaluations every 6-12 months, as well as periodic serum calcium levels (part of a routine chemistry panel) are also part of the monitoring process. Patients are encouraged to work with their physician-coaches on these issues.

3. Calcium citrate

• 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.4

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 the reading of Ken Cooper’s Antioxidant Revolution as well as Barry Sears’s Anti-Aging Zone for detailed exercise programs and for 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 is known to have this anti-angiogenesis effect as does genistein and calorie restriction. Other agents that have an effect on cancer cell invasiveness include green tea polyphenols (GTP). Green and black teas 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:

1. epicatechin (EC)
    
2. epigallocatechin (EGC)
    
3. epicatechin gallate (ECG)
    
4. epigallocatechin gallate (EGCG)

Of these four factions, the gallate catechin, EGCG, is the most important to the PC patient. Pharmacologic activity extends beyond its actions as an antioxidant and free-radical scavenger. Epigallocathechin-3 gallate (EGCG) acts against urokinase, an enzyme often found in large amounts in human cancers.5 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. EGCG attaches to urokinase and prevents these actions.

GTP also inhibit ornithine decarboxylase (ODC) resulting in a decrease in polyamine synthesis and cell growth.6

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.7 They also inhibit accessory sex gland growth in the rat. 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 low in Japan and other Asian countries. This is in contrast to the common occurrence of metastatic PC in Europe and the United States. One possible explanation is that EGCG consumption of green tea and genistein in Asian countries prevents the progression and metastasis of PC cells. This might explain the lower mortality of PC and breast cancer in Asia compared to Western countries.

Figure 1. EGCG on PC-3 Growth after Liao et al.8

In a study by Liao et al.8 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. (See Figure 1) The injection of EGCG slowed tumor growth when administered to the control mice on day 14 while tumor growth 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.8 The galloyl group of EGCG appears to be necessary for inhibition of tumor growth since EGC is not active. EGCG accounts for ~ 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. Life Extension Foundation makes a green tea 83–95% 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 4-10 cups of Japanese green tea. Green Tea 95% lightly-caffeinated extract contains 10-20 mg of caffeine or is available in decaffeinated form. We suggest that GT 83-95% be used at a dose of one capsule three 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.

Lycopenes
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 six-year study by Giovannucci et al 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 per week in several forms (sauce, juice, raw or on pizza) had a 41% reduction in PC while those who ate four to seven servings per week had a 22% reduction.9 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 in Table 1 below.

Table 1. Lycopenes

The only other food associated with a low prostate cancer risk was strawberries. One serving (0.5 cup) of strawberries was associated with a significantly decreased risk of prostate cancer.9 Strawberries are not in the lycopene family.

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.10 Interestingly, the source of lycopene was a beta-carotene rich algae called Dunaliella bardawil.

Recently, Kucuk et al reported on thirty men with localized PC scheduled for radical prostatectomy. They were randomly assigned to receive either 15 mg of lycopene (Lyc-O-Mato™, LycoRed, BeerSheva, Israel) orally twice daily or no intervention for three weeks prior to surgery. Prostate specimens were step-sectioned, entirely embedded, and evaluated for pathologic stage, Gleason score, the volume of PC as well as the extent of PIN (a pathologic finding often associated with PC) in the gland. The specimens were also examined by 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 the time of RP, eight of 12 patients (67%) within the treated group had organ confined PC and 84% had tumors less than 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 by about 20% in the intervention group (P=0.02) but not in the control group. The results suggest a role for lycopene in PC prevention.11 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. We see no reason not to include this at any time.

Summary
We live in a world of oxidative damage, loaded with stressors, and coupled with the hormonal imbalance of aging. In our attempts to extend life, we can manipulate such an environment. The PC patient can be involved with integrative therapies to augment the conventional treatment of this disease. A protein-carbohydrate balanced diet (low in saturated fat), and moderate exercise, vitamin E, and selenium represents a foundation upon which to add agents such as genistein, lycopene, green tea and silymarin. The supporting structure of the body must be maintained with modest amounts of calcium, vitamin D and bisphosphonates. The individual patient may need to be fine-tuned with specific antioxidants to address issues unique to that patient.

We will attempt to update these nutritional findings at least annually. Please note that this is far from an exhaustive review of the nutritional aspects of prostate cancer. As more is learned about the optimal dosage and duration of these substances, our recommendations will be refined. The blessing of such an approach for PC is that the use of the above agents is also conducive to outstanding cardiovascular and mental health.

References

1. Geller J, Sionit L, Partido C, et al: Genistein inhibits the growth of human-patient BPH and prostate cancer in histoculture. Prostate 34:75-9, 1998.

2. Gross C, Stamey T, Hancock S, Feldman D: Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3. J Urol. 159:2035-2039, 1998.

3. Koike M, Elstner E, Campbell MJ, et al: 19-nor-hexafluoride analogs of vitamin D3: A novel class of potent inhibitors of proliferation and induction of p27/Kip1 in human breast cancer cell lines. Proc Annu Meet Am Assoc Cancer Res 38:A579, 1997.

4. Blumsohn A, Herrington K, Hannon RA, et al: The effect of calcium supplementation on the circadian rhythm of bone resorption. J Clin Endocrinol Metab 79: 730-735, 1994.

5. Jankun J, Selman SH, Swiercz R, et al: Why drinking green tea could prevent cancer. Nature 387:561, 1997.

6. Carlin BI, Pretlow TG, Pretlow TP, et al. Green tea polyphenols inhibit growth of PC xenograft cwr-22 and decrease ornithine decarboxylase activity: implications for PC chemoprevention. J Urol 155: 510A, 1996.

7. Liao S, Hiipakka, RA: Selective inhibition of steroid 5 µ-reductase [5AR] by tea epicatechin-3-gallate and epigallocatechin-3-gallate. Biochemical and Biophysical Research Communications; 214:833-838,1995.

8. Liao S, Umekita Y, Guo J et al. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Letters 96:239-243, 1995.

9. Giovannucci E, Ascherio A, Rimm E, et. al: Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87:1767-1776, 1995.

10. Nagasawa H, Mitamura T, Sakamoto S. et. al: Effects of lycopene on spontaneous mammary tumour development in SHN virgin mice. Anticancer Res 15:1173-8, 1995.

11. Kucuk 0, Sakr W, Sarkar FH, et al: Lycopene supplementation in men with localized prostate cancer (PCa) modulates grade and volume of prostatic intraepithelial neoplasia (PIN) and tumor, level of serum PSA and biomarkers of cell growth, differentiation and apoptosis. Proc Annu Meet An Assoc Cancer Res. 40:A2706, 1999.

Prostate Cancer Research Institute (PCRI)

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