The Potential for Prostate Cancer Chemoprevention

FUTURE OPTIONS IN CAP TREATMENT The Potential for Prostate Cancer Chemoprevention Otis W. Brawley, MD Winship Cancer Institute, Emory University, Atlanta, GA The dramatic international variation in prostate cancer incidence and mortality rates suggests that changeable environmental factors exert an influence. This has prompted a search for ways to prevent the disease. Epidemiologic studies suggest that dietary factors such as the carotenoid lycopene, selenium, vitamin E, and high intake of fat have roles in prostate cancer risk. Several studies show that impairment of androgen synthesis lowers the risk of prostate cancer. 5--reductase inhibitors such as finasteride have been shown to decrease prostate size by decreasing androgenic stimulation to the prostate. Other promising, but less developed, interventions include vitamin D supplements and modification of diet. Any manipulation to decrease one’s relative risk of prostate cancer will by necessity have to be given to a large proportion of men who would never develop prostate cancer even without the intervention. To be acceptable, a successful preventive intervention should have few or no side effects; some additional benefits would be useful. All potential preventive interventions will need to be rigorously evaluated before they can be advocated for prostate cancer prevention. [Rev Urol. 2002;4(suppl 5):S11–S17] © 2002 MedReviews, LLC Key words: Androgens • Chemoprevention • Finasteride • Prostate cancer • 5--reductase inhibitors tudies of the incidence and mortality of prostate cancer in various countries suggest that changeable environmental elements are important in its etiology.1 Studies have demonstrated that migration from areas of low risk to areas of high risk is associated with an increased risk of prostate cancer in the migrants compared to that in men remaining in the lower-risk country of origin.1 In migration studies done before the prostate-specific antigen (PSA) screening era, Japanese migrants to the United States were shown to have a marked increase in prostate cancer, although the incidence in Japanese Americans remains less than that in whites.2 Prostate cancer incidence rates are very low in eastern Europe and Russia, but Polish and Russian migrants to the United States acquire higher rates after migration. S VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S11 Potential Chemoprevention for CaP continued Although population studies do suggest that there may be a genetic component to some prostate cancers, there are likely to be numerous environmental components to prostate carcinogenesis and prostate cancer prevention.3 Nutritional factors in defined populations, especially high animal fat and high dairy intake, have been correlated with a greater risk of disease.4 It has been suggested that populations with higher circu- growth and division. Inhibition or slowing of this process can potentially prevent cancers from becoming clinically significant.12 Although chemoprevention of cancer is a relatively new concept, the chemoprevention of other diseases is common, although often not called by that name. The prevention of heart disease with lipid-lowering drugs is widely accepted, as is the prevention of tooth decay with fluoride or osteo- There are likely to be numerous environmental components to prostate carcinogenesis and prostate cancer prevention. lating levels of androgens and insulin-like growth factors tend to have a higher risk of prostate cancer.5,6 Levels of circulating androgens and of insulin-like growth factor are affected by diet.7,8 In at least one case-control study with age-adjusted analyses, there were positive associations of prostate cancer risk (all stages combined) with total energy intake as well as with total fat intake.9 There are also studies in the literature showing correlations between populations with higher consumption of selenium and vitamin E, fructose/fruits, and tomatoes and those with lower risk of prostate cancer.10 These observations, combined with an improved understanding of the biology of prostate cancer, provide numerous leads in the effort to find workable prostate cancer chemoprevention.11 Chemoprevention Chemoprevention is a word first used in the mid 1970s. It means the administration of agents to prevent induction and to inhibit or delay the progression of cancers. Important to the concept of chemoprevention is the fact that carcinogenesis is a process over time, involving cellular S12 VOL. 4 SUPPL. 5 2002 porosis in postmenopausal women with estrogen.13 These are all examples of chemoprevention of disease. Because chemoprevention of cancer would involve the treatment of healthy subjects, successful agents must have low toxicity.14–16 Because their purpose is to keep something from occurring, definitive clinical studies to demonstrate their efficacy are necessarily randomized, blinded, long term, and large. Androgen and Prostate Cancer It has been suggested that androgen is an important promoter of prostate cancer. It has long been appreciated androgen or higher sensitivity to androgens are at greater risk of prostate cancer. Dietary Intervention Dietary intervention is not classically considered chemoprevention, but it could be very important in the prevention of prostate cancer. Some dietary elements may cause prostate cancer; elements in some diets may prevent prostate cancer. The latter elements, if identified, are excellent candidates for sources of chemopreventive drugs. Several studies support a positive correlation between some aspect or component of animal fat and prostate cancer risk.1,2 Armstrong and Doll compared the prostate cancer death rate and average fat consumption in 32 countries.18 Populations with diets high in fat have increased prostate cancer relative risks by a factor of 1.6 to 1.9.19–23 These studies may be limited by the inability to control adequately for potential confounders. As discussed above, fat consumption may be inversely correlated with increased consumption of some chemopreventive agents, and increased fat consumption may be a marker for some other etiologic factor. Although it has been shown that a Western diet increases serum andro- Because chemoprevention of cancer would involve the treatment of healthy subjects, successful agents must have low toxicity. that prostate cancer is an androgendriven illness. Removal of androgenic stimulation has been used to treat metastatic disease for some time.17 Populations with impaired androgen metabolism, such as those with congenital 5--reductase deficiency, do not develop prostate cancer. There is also the suggestion that populations with higher circulating levels of REVIEWS IN UROLOGY gen levels, the precise mechanism of increased production of sexual hormones is not well understood.24 It is, however, established that a high-fat diet can increase hormonal bioavailability. Plasma concentrations of fatty acids are increased with increasing consumption of fat, and these plasma fatty acids inhibit binding of gonadal steroids to sex hormone– Potential Chemoprevention for CaP binding globulin.25 A fatty diet may increase prostate cancer risk by causing long-term androgenic stimulation. The dietary fat hypothesis suggests that a potential preventive strategy is to lower androgenic stimulation. This could be accomplished by drug therapy or by diet modification. In population studies, diets high in fiber and presumably lower in fat are associated with lower incidences of prostate cancer.26 A low-fat, high- as 10–6 molar. This level inhibits the growth of tumor cells in vivo.30 It is unclear how these laboratory observations translate into human biology. In a nested case-control study of selenium levels in the toenails of men with prostate cancer compared with those of matched controls, higher selenium levels were associated with a 50% reduction in risk of metastatic prostate cancer.31 Several prospective epidemiologic studies question the Populations with impaired androgen metabolism, such as those with congenital 5-a-reductase deficiency, do not develop prostate cancer. fiber diet increases fecal excretion of gonadal hormones and possibly lowers serum androgen levels.27 The diet in many Asian countries is especially high in plant products and phytoestrogens. Plant-based weak estrogens such as isoflavonoids may prevent prostate cancer by weakly binding androgen hormone receptors in the prostate, thereby interfering with androgenic stimulation of prostate cells.28 One case-control study suggests that populations consuming high amounts of soy milk have lower rates of prostate cancer.29 The most prominent isoflavonoid to be a candidate preventive agent is genistein.28 Selenium Oxidative stress has been proposed as a promoter of the process of carcinogenesis. Oxidation can lead to genetic mutations, which can in turn lead to malignancy. Antioxidants have been suggested as potential preventive agents for a number of cancers. Selenium is found in many vegetables and grains grown in selenium-rich soil. It has antioxidant activity and may have other direct effects on tumor cells. Serum selenium concentrations in humans living in high-selenium areas may be as high chemopreventive worth of selenium. They show an inverse association between prostate cancer risk and selenium content of prediagnostically collected toenail clippings32 or serum.33 In a randomized, placebo-controlled trial to assess the ability of 200 mg/d of selenized yeast to decrease skin cancer, a secondary analysis of endpoints shows a statistically significant reduction in prostate cancer incidence of 63%.34 Vitamin E Alpha-tocopherol is the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods. It is a potent antioxidant and has been suggested and -carotene, or a placebo daily for 5–8 years. At the conclusion of the trial there was a median of 6.1 years of therapy. In this lung cancer prevention trial there was a serendipitous finding of a 32% decrease in prostate cancer incidence among males who received vitamin E alone.37 While the ATBC study suggests that -tocopherol administration reduces prostate cancer risk, there are inconsistent observational epidemiologic studies concerning serum levels of -tocopherol. Some studies even suggest an inverse relationship between blood -tocopherol levels and prostate cancer risk.32,34,38,39 Carotenoids A number of carotenoids are known to have antioxidant activity. Although a number of reports support a protective role for carotenoids in prostate cancer prevention, the literature is inconsistent. This is partially due to the inconsistent methods used to measure carotenoid content in foods.40 The intake of vitamin A from plant sources is associated with decreased prostate cancer risk, whereas the intake of vitamin A from animal sources may be associated with increased prostate cancer risk.41 These findings, if accurate, may be due to a lower fat content in the diets of men with high plant vitamin A It has been shown that a Western diet increases serum androgen levels. as potentially preventive of several cancers, particularly lung cancer.35 In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (the ATBC Study),36 a total of 29,133 men aged 50–69 years who smoked five or more cigarettes daily were randomized to receive -tocopherol (50 mg), -carotene (20 mg), -tocopherol intake and a higher fat content in the diets of men with high animal vitamin A intake. Prospective epidemiologic studies also suggest that lycopene, a vitamin A analog, is associated with a decreased risk of prostate cancer.42,43 Lycopene is commonly found in tomato products. Cooking with oils, such as in the preparation of tomato VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S13 Potential Chemoprevention for CaP continued sauces and tomato paste, increases the bioavailability of lycopene.44–46 Vitamin D Geographic differences in sun exposure lead to varying amounts of vitamin D in populations and variances in calcium level. There are epidemiologic correlations between lack of sun exposure at colder latitudes and increased prostate cancer risk. In a case-control study, men with high levels of serum calcium (both from dairy products and from supplements) had four to five times the risk of metastatic prostate cancer of men with lower levels.47 This has led to interest in vitamin D and vitamin D analogs as chemopreventive agents.48 The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits growth of both primary cultures of human prostate cancer cells and cancer cell lines, but the mechanism by which the cells’ growth is inhibited has not been clearly defined. Initial studies suggest that calcitriol alters cell cycle progression and may also initiate apoptosis. One of the disadvantages of vitamin D is the side effects, such as hypercalcemia at doses above physiologic levels. Analogs of calcitriol have been developed that have comparable or more potent antiproliferative effects but are less likely to produce hypercalcemia.49 Drug Therapy Nonsteroidal Anti-inflammatory Drugs The nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and sulindac, may have prostate cancer chemopreventive activity. In a casecontrol study of 417 prostate cancer patients and 420 group-matched control subjects, regular daily use of over-the-counter NSAIDs, ibuprofen or aspirin, was associated with a 66% reduction in prostate cancer risk (odds ratio [OR], 0.34; 95% confidence S14 VOL. 4 SUPPL. 5 2002 interval [CI], 0.23-0.58; P < .01). The risk of prostate cancer was also significantly reduced in men who reported taking prescription NSAIDs (OR, 0.35; 95% CI, 0.15-0.84; P < .05).6–8,50 The cyclooxygenase-2 (COX-2) inhibitors provide great promise in the prevention of prostate and colon cancer. 5-Alpha-Reductase Inhibitors If long-term androgenic stimulation is important to prostate carcinogenesis, decreasing this stimulation through drug therapy may impede carcinogenesis. Androgenic blockers such as flutamide, bicalutamide, and cancer development is compared to that of the half that was not treated with the 5--reductase inhibitor. The fact that these studies require longterm androgenic stimulation (administration of testosterone) in itself suggests that decreasing such stimulation will prevent prostate cancers. Finasteride (trade name Proscar) was the first 5--reductase inhibitor to enter human trials. It lowers intraprostatic dihydrotestosterone levels while causing intraprostatic testosterone levels to increase slightly.13,59,60 Because DHT is more potent than testosterone, this results in a net decrease in androgenic stimulation. Finasteride (trade name Proscar) was the first 5--reductase inhibitor to enter human trials. nilutamide have too many side effects to be of practical use in an asymptomatic, healthy population. Dihydrotestosterone (DHT) is the principal androgen responsible for normal and hyperplastic growth of the prostate gland. DHT is 10 times more potent an androgen than testosterone. Inhibition of 5-reductase decreases the amount of DHT in prostate cancer tissue, thereby lowering androgenic stimulation to the prostate. Systemic androgenic stimulation is only mildly affected.51 In vitro studies suggest that 5-reductase inhibition slows the growth of previously established prostate cancer cell lines.52,53 In studies of prostate cancer tumors grafted into animals, 5--reductase inhibition impedes tumor implantation and growth.54–58 In studies in which rats are given a cancer initiator and high-dose testosterone, 5--reductase inhibition can prevent actual prostate carcinogenesis. In these studies, half the rats are treated with a 5--reductase inhibitor and their rate of prostate REVIEWS IN UROLOGY In clinical trials and in common usage, finasteride has been shown to have few side effects. In a randomized, double-blind study, a very small proportion of men on therapy reported impotence and/or loss of libido compared to men who received placebo.60 Finasteride is effective in the treatment of moderate benign prostatic hyperplasia (BPH).55,58,61 It was approved by the U.S. Food and Drug Administration for treatment of BPH in 1992 and for treatment of male pattern baldness in 1997. Other Agents The relationships between prostate cancer and consumption of vitamin C, vitamin B1, vitamin B2, vitamin B3, calcium, zinc, protein, and carbohydrates have been investigated. No clear association exists between these common dietary factors and prostate cancer.42 Certain drugs have been suggested as chemopreventive agents based on theory and limited in vitro data. These are nonclassic antioxidant Potential Chemoprevention for CaP agents, including the polyphenols, the isothiocyanates, difluoromethylornithine (DFMO [Eflornithine]), oltipraz, and N-acetylcysteine.62,63 These drugs have not been rigorously assessed in clinical trials. Clinical Prevention Trials The potential for selenium and tocopherol for prostate cancer prevention is intriguing. These drugs have minimal side effects. They are being explored in a prospective randomized clinical trial entitled Selenium and Vitamin E Cancer Prevention Trial (SELECT). This trial has a 2 × 2 design in which one fourth of all participants will be randomized to receive yeast-derived selenium daily, one fourth will receive vitamin E, one fourth will receive both drugs, and one fourth will receive placebo. The trial will enroll more than 32,000 men and run for more than a dozen years. Its design has 90% power to detect a 25% difference in incidence. SELECT began in 2001. The Prostate Cancer Prevention Trial (PCPT) began in 1993 and should end in early 2004. More than 18,800 healthy men of age 55 years and older were randomized to finasteride (5 mg/day or placebo) from 1993 to 1997. All the men are screened annually for prostate cancer with digital rectal examination and serum PSA assay. Serum PSA is measured in a central laboratory. The primary endpoint of PCPT is the reduction of biopsy-proven prostate cancer incidence over a 7-year period (resulting in a reduction of the period prevalence of the disease). The impact of finasteride on serum PSA does complicate the trial, as both groups of participants must have equal risk of prostate cancer diagnosis through screening. Doubling the PSA levels in finasteride-treated patients allows appropriate interpretation of PSA values and does not mask the detection of prostate can- or a drug, has been found to clearly decrease prostate cancer risk. No intervention can be definitively proven efficacious without a randomized clinical trial. Because these trials are trying to demonstrate that something does not happen, they are large, expensive, and long in duration. The size of the trials makes a mortality endpoint prohibitive, so they are designed to assess the incidence of diagnosed disease. This is an unfortunate but necessary shortcoming. Ultimately, phase II trials using Men with genetic predisposition to prostate cancer may not benefit any more from some successful interventions than those at risk for sporadic prostate cancer. cer.64,65 At 7 years, all available participants will undergo a sextant biopsy to determine the period prevalence of prostate cancer. The trial has 90% power to detect a 25% reduction in the period prevalence of biopsy-proven disease using a twosided test with  = .05. The study will end in late 2004.66 In addition to its primary objective, the PCPT will provide opportunities to better understand prostate cancer biology and the prevention and treatment of BPH.67,68 Conclusion The prevention of prostate cancer is a relatively new concept. No intervention, through dietary modification validated surrogate markers of prostate cancer incidence are critical for the efficient evaluation of a preventive strategy. Validation of these markers will itself require large, long-term randomized trials. Markers such as the regression of prostatic intraepithelial neoplasia as measured in radical prostatectomy specimens or decline in PSA both in men with intact prostates and in men with relapse after radical prostatectomy have been suggested. Again, the utility of these methods will remain controversial until validated.69,70 Eventually one of the drugs above or several in combination may be found to decrease an individual’s risk Main Points • Environmental elements appear to be important in the etiology of prostate cancer. • Risk of prostate cancer may be associated with serum androgen and insulin-like growth factor levels, which are affected by dietary selenium, vitamin E, lycopene, and fat levels. • A high-fat diet can increase hormonal bioavailability, and prostate cancer is an androgen-driven illness. • Nonsteroidal anti-inflammatory drugs, especially cyclooxygenase-2 inhibitors, show promise for prevention of prostate cancer. • Finasteride lowers dihydrotestosterone levels and slightly raises testosterone levels in the prostate, yielding a net decrease in androgenic stimulation, and has few side effects. VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S15 Potential Chemoprevention for CaP continued of prostate cancer. Questions for research include who would benefit from such drugs. Men with genetic predisposition to prostate cancer may not benefit any more from some successful interventions than those at risk for sporadic prostate cancer. Until an efficacious prostate cancer chemopreventive agent is found, scientists and physicians must be careful not to mislead the lay public. We must stress what is known, what is not known, and what is believed about chemoprevention. 18. 19. 20. 21. 22. 23. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. S16 Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer. 2000;85:60–67. Haenszel W, Kurihoro M. Studies of Japanese migrants. J Natl Cancer Inst. 1969;40:43–68. Glover FEJ, Coffey DS, Douglas LL, et al. The epidemiology of prostate cancer in Jamaica. J Urol. 1998;159:1984–1986. Giovannucci E. Insulin-like growth factor-I and binding protein-3 and risk of cancer. Horm Res. 1999;51(suppl 3):34–41. Yu H, Berkel H. Insulin-like growth factors and cancer. J La State Med Soc. 1999;151:218–223. Harman SM, Metter EJ, Blackman MR, et al. Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein 3, and prostate-specific antigen as predictors of clinical prostate cancer. J Clin Endocrinol Metab. 2000;85:4258–4265. Smith GD, Gunnell D, Holly J. Cancer and insulin-like growth factor-I: a potential mechanism linking the environment with cancer risk. BMJ. 2000;321:847–848. Allen NE, Appleby PN, Davey GK, Key TJ. Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men. Br J Cancer. 2000;83:95–97. Andersson SO, Wolk A, Bergstrom R, et al. Energy, nutrient intake and prostate cancer risk: a population-based case-control study in Sweden. Int J Cancer. 1996;68:716–722. Giovannucci E, Clinton SK. Tomatoes, lycopene, and prostate cancer. Proc Soc Exp Biol Med. 1998;218:129–139. Giovannucci E. Selenium and risk of prostate cancer. Lancet. 1998;352:755–756. Kelloff GJ, Lieberman R, Steele VE, et al. Chemoprevention of prostate cancer: concepts and strategies. Eur Urol. 1999;35:342–350. Greenwald P, Kelloff G, Burch-Whitman C, Kramer BS. Chemoprevention. CA Cancer J Clin. 1995;45:31–49. Redman C, Scott JA, Baines AT, et al. Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines. Cancer Lett. 1998;125:103–110. Hong WK, Lippman SM. Cancer chemoprevention. J Natl Cancer Inst Monogr. 1995;17:49–53. Lippman SM, Benner SE, Hong WK. Cancer chemoprevention. J Clin Oncol. 1994;12:851–873. Huggins C, Hodges CV. Studies on prostate can- VOL. 4 SUPPL. 5 2002 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. REVIEWS IN UROLOGY cer. I: The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297. Armstrong B, Doll R. Enviromental factors and cancer incidence and mortality in different countries with special reference to dietary practices. Int J Cancer. 1975;15:617–631. Kolonel LN, Nomura AMY, Hinds MW, et al. Role of diet in cancer incidence in Hawaii. Cancer Res. 1983;43(5 suppl):2397–2402. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chron Dis. 1979;32:563–576. Severson RK, Grove JS, Nomura AM, Stemmerman GN. Body mass and prostatic cancer: a prospective study. BMJ. 1988;297:713–715. Kaul L, Heshmat MY, Kovi J, et al. The role of diet in prostate cancer. Nutr Cancer. 1987;9:123–128. Severson RK, Nomura AMY, Grove JS, Stemmermann GN. A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res. 1989;49:1857–1860. Hayes RB, Ziegler RG, Gridley G, et al. Dietary factors and risks for prostate cancer among blacks and whites in the United States. Cancer Epidemiol Biomarkers Prev. 1999;8:25–34. Bruning PF, Bonfrer JMG. Free fatty acid concentrations correlated with the available fraction of estradiol in human plasma. Cancer Res. 1989;46:2606–2609. Slattery ML, Schumacher MC, West DW, et al. Food consumption trends between adolescent and adult years and subsequent risk of prostate cancer. Am J Clin Nutr. 1990;52:752–757. Pusateri DJ, Roth WT, Ross JK, Shultz TD. Dietary and hormonal evaluation of men at different risks for prostate cancer: plasma and fecal hormone-nutrient interrelationships. Am J Clin Nutr. 1990;51:371–377. Evans BA, Griffiths K, Morton MS. Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol. 1995;147:295–302. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control. 1998;9:553–557. Webber MM, Perez-Ripoll EA, James GT. Inhibitory effects of selenium on the growth of DU-145 human prostate carcinoma cells in vitro. Biochem Biophys Res Commun. 1985;130:603–609. Yoshizawa K, Willett WC, Morris SJ, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst. 1998;90:1219–1224. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92:2018–2023. Nomura AM, Lee J, Stemmermann GN, Combs GF. Serum selenium and subsequent risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2000;9:883–887. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. Nutritional Prevention of Cancer Study Group [published correction appears in JAMA. 1997;277:1520]. JAMA. 1996;276:1957–1963. Shklar G, Oh SK. Experimental basis for cancer prevention by vitamin E. Cancer Invest. 2000;18:214–222. 36. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440–446. 37. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029–1035. 38. Hsing AW, Comstock GW, Abbey H, Polk BF. Serologic precursors of cancer: retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst. 1990;82:941–946. 39. Eichholzer M, Stahelin HB, Gey KF, et al. Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year followup of the prospective Basel study. Int J Cancer. 1996;66:145–150. 40. Mangels AR, Holden JM, Beecher GR, et al. Carotenoid content of fruits and vegetables: an evaluation of analytic data. J Am Diet Assoc. 1993;93:284–296. 41. Kolonel LN, Nomura AM, Cooney RV. Dietary fat and prostate cancer: current status. J Natl Cancer Inst. 1999;91:414–428. 42. Giovannucci E, Clinton SK. Tomatoes, lycopene, and prostate cancer. Proc Soc Exp Biol Med. 1998;218:129–139. 43. Zackheim HS. Re: Tomatoes, tomato-based products, lycopene, and prostate cancer: review of the epidemiologic literature [letter; comment]. J Natl Cancer Inst. 1999;91:1331. 44. Giovannucci E, Clinton SK. Tomatoes, lycopene, and prostate cancer. Proc Soc Exp Biol Med. 1998;218:129–139. 45. Gann PH, Ma J, Giovannucci E, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res. 1999;59:1225–1230. 46. Giovannucci E, Ascherio A, Rimm EB, et al. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst. 1995;87:1767–1776. 47. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality: evidence for a protective effect of ultraviolet radiation. Cancer. 1992;70:2861–2869. 48. Crawford ED, Fair WR, Kelloff GJ, et al. Chemoprevention of prostate cancer: guidelines for possible intervention strategies. J Cell Biochem Suppl. 1992;16H:140–145. 49. Blutt SE, Weigel NL. Vitamin D and prostate cancer. Proc Soc Exp Biol Med. 1999;221:89–98. 50. Nelson JE, Harris RE. Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep. 2000;7:169–170. 51. Montironi R, Mazzucchelli R, Pomante R, et al. Immunohistochemical expression of pi class glutathione S-transferase in the basal cell layer of benign prostate tissue following chronic treatment with finasteride. J Clin Pathol. 1999;52:350–354. 52. Bologna M, Muzi P, Biordi L, et al. Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. Urology. 1995;45:282–290. 53. Delos S, Iehle C, Martin PM, Raynaud JP. Inhibition of the activity of ‘basic' 5 alphareductase (type 1) detected in DU 145 cells and 35. Potential Chemoprevention for CaP 54. 55. 56. 57. 58. expressed in insect cells. J Steroid Biochem Mol Biol. 1994;48:347–352. Tsukamoto S, Akaza H, Imada S, et al. Chemoprevention of rat prostate carcinogenesis by use of finasteride or casodex. J Natl Cancer Inst. 1995;87:842–843. Roehrborn CG, Boyle P, Bergner D, et al. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology. 1999;54:662–669. Zaccheo T, Giudici D, di Salle E. Effect of turosteride, a 5-alpha-reductase inhibitor, on the Dunning R3327 rat prostatic carcinoma. Prostate. 1997;30:85–91. Tsukamoto S, Akaza H, Onozawa M, et al. A five-alpha reductase inhibitor or an antiandrogen prevents the progression of microscopic prostate carcinoma to macroscopic carcinoma in rats. Cancer. 1998;82:531–537. Homma Y, Kaneko M, Kondo Y, et al. Inhibition of rat prostate carcinogenesis by a 5alphareductase inhibitor, FK143. J Natl Cancer Inst. 1997;89:803–807. 59. 60. 61. 62. 63. 64. Geller J. Clinical review: 67: Approach to chemoprevention of prostate cancer. J Clin Endocrinol Metab. 1995;80:717–719. Stoner E. Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology. 1994;43:284–292. Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two-year Study. Can Med Assoc J. 1996;155:1251–1259. Thompson IM, Coltman CA, Brawley OW, Ryan A. Chemoprevention of prostate cancer. Semin Urol. 1995;13:122–129. Singh DK, Lippman SM. Cancer chemoprevention. II. Hormones, nonclassic antioxidant natural agents, NSAIDs, and other agents. Oncology (Huntingt). 1998;12:1787–1800. Oesterling JE, Roy J, Agha A, et al. Biologic variability of prostate-specific antigen and its usefulness as a marker for prostate cancer: effects of finasteride. The Finasteride PSA Study Group. Urology. 1997;50:13–18. 65. 66. 67. 68. 69. 70. Guess HA, Gormley GJ, Stoner E, Oesterling JE. The effect of finasteride on prostate specific antigen: review of available data. J Urol. 1996;155:3–9. Coltman CAJ, Thompson IMJ, Feigl P. Prostate Cancer Prevention Trial (PCPT) update. Eur Urol. 1999;35(5–6):544–547. Zaccheo T, Giudici D, di Salle E. Effect of early treatment of prostate cancer with the 5-alphareductase inhibitor turosteride in Dunning R3327 prostatic carcinoma in rats. Prostate. 1998;35:237–242. Thompson IM, Coltman CAJ, Crowley J. Chemoprevention of prostate cancer: the Prostate Cancer Prevention Trial. Prostate. 1997;33:217–221. Montironi R, Mazzucchelli R, Marshall JR, Bartels PH. Prostate cancer prevention: review of target populations, pathological biomarkers, and chemopreventive agents. J Clin Pathol. 1999;52:793–803. Cote RJ, Skinner EC, Salem CE, et al. The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels. Br J Cancer. 1998;78:413–418. VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S17