Opportunities for Prevention of Prostate Cancer: Genetics, Chemoprevention, and Dietary Intervention

FUTURE OPTIONS IN CAP TREATMENT Opportunities for Prevention of Prostate Cancer: Genetics, Chemoprevention, and Dietary Intervention Eric A. Klein, MD Head, Section of Urologic Oncology, Urological Institute, Cleveland Clinic Foundation, Cleveland, OH At least five susceptibility loci for the development of prostate cancer have been identified in the last several years. Although the specific genes involved have yet to be fully characterized, these discoveries hold promise for the identification of individuals at risk for prostate cancer years before development of the disease. Individuals identified as at risk through simple genetic screening (ie, a test on peripheral blood) could have a modified screening schedule, be entered into clinical trials of chemoprevention or dietary modification, and/or be treated according to the clinical characteristics of the cancer associated with a particular gene. Several large chemoprevention trials that exploit underlying pathogenetic mechanisms for the development of prostate cancer are currently underway or about to open. The future of prostate cancer is in the genes and our ability to manipulate the molecular events they cause. [Rev Urol. 2002;4(suppl 5):S18–S28] © 2002 MedReviews, LLC Key words: Prostate cancer • Prevention • Chemoprevention • Genetics • Dietary supplementation rostate cancer has been the most common visceral malignancy in American men for the last decade. The estimated lifetime risk of disease is 16.6% for Caucasians and 18.1% for African Americans, with a lifetime risk of death of 3.5% and 4.3%, respectively.1 The dramatic increase in the number of cases and the steady increase in mortality from prostate cancer, which has only recently begun to decline, have piqued interest in developing ways of improving early diagnosis for initiation of therapy at a more curable stage. Although prostatespecific antigen (PSA)–based screening regimens have resulted in a substantial stage migration and greatly reduced the frequency of tumors that are metastatic P S18 VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY CaP Prevention: Genetics, Chemoprevention, and Diet Table 1 Familial Prostate Cancer: Epidemiologic Evidence Study Type Case-Control* No. Studies 8 Relative Risk 1.76–11 Case-Control† 5 0.64–7.5 Cohort (U.S.) 1 2.2 Cohort (Sweden) 1 1.7 *No. cases in relatives. †Percent cases versus controls with positive family history. Data from Bratt.5 at the time of diagnosis, there is no direct evidence that screening results in improved survival.2,3 Furthermore, the morbidity of various treatments remains substantial. An ideal method to reduce the mortality and morbidity of prostate cancer is through pri- Genetic Susceptibility to Prostate Cancer The first reports of a familial clustering of prostate cancer were published in the mid-20th century and suggested that the risk of developing prostate cancer was higher in those with an There is no direct evidence that PSA–based screening results in improved survival. mary prevention, either by reducing the number of life-threatening, clinically evident cases or by delaying the age at onset by 5, 10, or 15 years.4 Two developments in the study of prostate cancer may make the goal of primary prevention a reality in the near future. The first is the identification of susceptibility genes, which predispose a carrier to the development of prostate cancer. The second is the identification of naturally occurring substances and certain pharmacologic agents that hold promise for the prevention of prostate cancer. To this end, numerous largescale clinical trials are currently or will soon be underway. This review will highlight important observations in each field and present an integrated algorithm for the future management of prostate cancer. affected first-degree relative.5 Since then a number of other epidemiological studies of various designs have confirmed this observation (Table 1), suggesting a two-fold increase in relative risk in men with an affected father or brother, a three-fold increase in risk if the father or brother was affected by age 60, a four-fold increase in risk with an affected father and brother, and a five-fold increase in risk if from a nuclear family with three cases of prostate cancer, prostate cancer in three successive generations, or two relatives with prostate cancer prior to age 55.5 Hereditary forms of prostate cancer probably account for only 5%–10% of all prostate cancers. In 1996, Smith and colleagues published the results of a genome-wide search with linkage analysis, which for the first time mapped a specific region of the genome with the risk of prostate cancer.6 These authors mapped a prostate cancer susceptibility gene to chromosome 1q24-25 and named it HPC1, for hereditary prostate cancer gene 1. Two subsequent studies have confirmed this linkage, but several others have not. Linkage with HPC1 occurs more frequently in families with early-onset prostate cancer and in those with many affected family members (Table 2). Cancers linked to HPC1 have been reported to present with higher-grade tumors at more advanced stages, although there are no reported histological differences with sporadic cancers. Based on positional cloning analysis of HPC1–linked families, HPC1 has been tentatively identified as the pro-apoptotic gene RNaseL.7 A second susceptibility locus called HPC2 is located on chromosome 17p, and two studies have reported an association with missense mutations in the ELAC2 gene at this location in hereditary prostate cancer families.8,9 However, several other reports have Table 2 Characteristics of HPC1 • Located on 1q24-25 • Associated with early age of onset • Associated with many affected family members • May present with tumors of higher grade and more advanced stage VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S19 CaP Prevention: Genetics, Chemoprevention, and Diet continued Table 3 Characteristics of PCaP • Located on 1q42.2-43 • Associated with early age of onset • Phenotype unknown • Structure and function unknown Table 4 Characteristics of HPCX • Located on Xq27-28 • Phenotype unknown • Structure and function unknown • Not the androgen receptor not confirmed linkage to HPC2, and its importance in hereditary cancers remains uncertain.10,11 A third site of linkage with familial prostate cancer, located distal to HPC1 at 1q42.2-43 and named PCaP, was identified by a French group in 1998 (Table 3).12 This gene is also associated with early age of onset, but its existence has not yet been confirmed and nothing has been reported about its structure, function, or phenotypic characteristics. Table 5 Characteristics of CAPB • Located on 1p36 • Frequent loss of heterozygosity in central nervous system tumors • Not linked to age of onset • Linked to family history of central nervous system tumors • Structure and function unknown S20 VOL. 4 SUPPL. 5 2002 A fourth prostate cancer susceptibility gene located on chromosome X, named HPCX, was also recently reported (Table 4).13 X-linked inheritance of prostate cancer has long been suspected because of epidemiologic evidence suggesting the relative risk of prostate cancer was higher in men with an affected brother than an affected father. HPCX may account for about 16% of hereditary cancers in North America, although aside from the fact that this gene is not the gene for the androgen receptor, little is known about its structure or function. A fifth susceptibility gene, called CAPB, located on chromosome 1p36, was reported in 1999 in families with a high incidence of central nervous system tumors (Table 5).14 This gene likely accounts for only a small percentage of hereditary prostate cancer. A sixth susceptibility locus, located at chromosome 16q23.2, was recently reported by our group and is currently under study.15 It will likely be some years before these and other susceptibility genes are identified, cloned, and sequenced, and their functional and phenotypic consequences are understood. However, because these genes occur in the germline DNA, their identification leads to the very real possibility of testing DNA for their presence from a sample of peripheral blood and determining an individual's risk for developing a hereditary form of prostate cancer. The ability to do so could influence the way individuals are screened and treated for prostate cancer. For example, an individual who is judged to be at increased risk of prostate cancer because of a family history could be screened for the presence of the known susceptibility genes. If he tests negative, he could be screened as those with no family history are screened, using PSA and digital rectal examination (DRE). However, if he tests positive, he might REVIEWS IN UROLOGY Family History Relative Risk High Low Genetic Screening Affected Frequent PSABased Screening Normal PSA-Based Screening Chemoprevention Prophylactic RX Figure 1. Potential future screening paradigm incorporating genetic susceptibility to prostate cancer. PSA, prostate-specific antigen; RX, treatment. consider prostate biopsy earlier than usual, and at more frequent intervals, to closely monitor for the development of cancer. Alternatively, individuals at high risk based on their genetic profile might enter clinical trials with agents or dietary interventions that might prevent the development of prostate cancer. This future screening paradigm is outlined in Figure 1. In a similar vein, certain hereditary prostate cancers may be associated with tumors that behave in a more aggressive fashion. For example, as mentioned earlier, tumors associated with HPC1 present at higher grade and at more advanced stages. Furthermore, several studies have suggested a higher incidence of treatment failure after radical prostatectomy or radiation therapy and a higher risk of metastatic disease in patients who report a history of prostate cancer in a first-degree relative.16–18 These observations suggest that knowing a patient’s genetic status may also dictate how aggressively he is treated. This future treatment paradigm is outlined in Figure 2. CaP Prevention: Genetics, Chemoprevention, and Diet What may constitute the best form of aggressive therapy in high-risk individuals remains to be determined. Chemoprevention of Prostate Cancer Chemoprevention of prostate cancer is based on an understanding of the underlying molecular events that lead to neoplastic growth. A number of hypotheses regarding the pathogenesis of prostate cancer have lead to several large clinical trials with oral agents meant to prevent its development. The largest such trial to date, the U.S. Prostate Cancer Prevention Trial (PCPT), was based on recognition that the androgenic milieu is important in the development of prostate cancer. Finasteride is a testosterone analogue that com- petitively inhibits the enzyme 5- reductase (type 2), which converts testosterone to dihydrotestosterone (DHT) and causes a profound reduction in circulating and cellular DHT.19 Finasteride inhibits growth of prostate cancer cells in vitro and is an active preventive agent in certain animal models of prostate carcinogenesis.20,21 The PCPT is an ongoing phase III, double-blind, placebo-controlled, randomized trial to determine the efficacy of finasteride in reducing the period prevalence of prostate cancer. The PCPT opened in 1993 and results are expected to be reported in 2004. The main risk factor for prostate cancer for the population of men included in the PCPT was age; eligible participants needed to be age 55 years or older and have a Genotype Predicted Aggressiveness Low Intermediate High Observation Standard RX Aggressive RX Figure 2. Future treatment paradigm based on genetically determined tumor aggressiveness status. RX, treatment. normal DRE and serum PSA less than 3 ng/mL. The relatively low incidence Table 6 Target Populations for Chemoprevention Trials Risk Group Specific Population Advantages Disadvantages Low General population • Easily definable • Readily available • Results widely applicable • Rate of progression slow • Requires large study population and long follow-up interval • Studies costly Intermediate African Americans • Higher risk than general population • Difficult to define • Difficult to recruit because of perceived bias Family history • Double or greater the risk of prostate cancer • Ascertainment bias • Risk varies with number of affected family members, age of onset, and degree of relatedness • Likely to be genetically heterogeneous HPC-1–linked • Genetically homogeneous • Identification invasive and costly • Affected subjects rare Other genes • Genetically homogeneous • Identification invasive and costly • Affected subjects rare • Risk of progression undefined High-grade PIN • Highest known risk • Sampling error • Diagnosis subjective • Uncommon Genetic High HPC-1, hereditary prostate cancer gene 1; PIN, prostatic intraepithelial neoplasia. VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S21 CaP Prevention: Genetics, Chemoprevention, and Diet continued of prostate cancer expected in this group dictated a long treatment time (7 years, after which all subjects will undergo a prostate biopsy) and a very large study group (18,000 men, a goal easily exceeded during the 3-year accrual period). As discussed above, the advent of genetic screening raises the possibility of identifying a group at much higher risk than the general population for developing prostate cancer and could result in chemoprevention trials that include only high-risk participants. Such trials could be performed at lower cost over shorter intervals, and could more rapidly assess the potential benefits of varying agents. Features other than genetic risk, such as the presence of high-grade prostatic intraepithelial neoplasia (PIN), could also be used to define high-risk populations (Table 6). Because genetic screening for prostate cancer is still a few years away, another large chemoprevention trial including age and race as risk factors opened in North America in July 2001. This trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), is based on recent research suggesting that these two antioxidants may prevent prostate cancer. Enthusiasm for selenium in the prevention of prostate cancer comes from the results of the clinical trial conducted by Clark and colleagues in the United States among individuals with low-to-normal selenium status.22 In this study, 1312 subjects with a prior history of skin cancer were randomized to receive 200 g/day of elemental selenium or placebo and followed for an average of 4.5 years for the development of basal or squamous cell carcinoma of the skin and other cancers. The study findings for the primary endpoint (nonmelanoma skin cancer incidence reduction) were negative. However, analysis of the data for S22 VOL. 4 SUPPL. 5 2002 secondary endpoints revealed that prostate cancer incidence was reduced by two thirds among those in the selenium-supplemented group, as compared with placebo, which had no effect. Interest in vitamin E comes from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC), a large, randomized, double-blind, placebo-controlled trial of -tocopherol (50 mg synthetic dl--tocopheryl acetate daily) and beta-carotene (20 mg daily) alone or in combination, which reported a protective effect of vitamin E for prostate cancer among 29,133 male smokers aged 50 to 69 years at entry.23 There was a statistically significant, 32% reduction in prostate cancer incidence in the vitamin E arm of this trial. The observed preventive effect appeared stronger for clinically evident cases (ie, stages B–D), where the incidence was decreased 40% in subjects receiving -tocopherol. Prostate cancer mortality data, though based on fewer events, suggested a similarly strong effect of 41% lower mortality. REVIEWS IN UROLOGY SELECT is designed as a phase III randomized, double-blind, placebocontrolled, population-based trial to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer.24 The trial is funded by the U.S. National Cancer Institute and will be coordinated by the Southwest Oncology Group, with participation from major cooperative groups in North America, including the Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, National Central Cancer Treatment Group, Radiation Therapy Oncology Group, Veterans Administration, and Canadian Urologic Oncology Group. SELECT will enroll 32,400 healthy men. The large sample size for this study will yield a 96% power to detect a 25% reduction in the incidence of prostate cancer in the selenium or vitamin E arms versus placebo, and 99% power to detect a 44% reduction in incidence in the combined selenium and vitamin E arm. SELECT opened for enrollment in July 2001 and as of June 1, 2002 had accrued more Table 7 Eligibility Criteria for SELECT • Age ≥55 years for Caucasians ≥50 years for African Americans • DRE not suspicious for prostate cancer • Total serum PSA ≤ 4.0 ng/mL • No prior history of prostate cancer or high-grade prostatic intraepithelial neoplasia (PIN) • No anticoagulation therapy, except low-dose aspirin • Normal blood pressure • Willing to restrict supplementation of selenium and vitamin E during participation SELECT, Selenium and Vitamin E Cancer Prevention Trial; DRE, digital rectal examination; PSA, prostate-specific antigen. CaP Prevention: Genetics, Chemoprevention, and Diet 44% reported use of a multivitamin, 35% took vitamin C or E, and 15% used antioxidant supplements at least three times per week.25 In addition to vitamin E and selenium, soy and lycopene appear promising as potential preventative agents. The evidence supporting their use is both epidemiologic and mechanistic. Pre-randomization Period (Minimum 28 days) Calendar Year 2001-2005 Randomization Calendar Year 2001-2013 Vitamin E + Vitamin E + Selenium + Placebo + Selenium Placebo Placebo Placebo Follow - up Prostate cancer, other cancer, death Figure 3. Design of the Selenium and Vitamin E Cancer Prevention Trial. than 11,500 participants. The results of the trial are expected in 2013. Inclusion criteria are listed in Table 7. Age eligibility is at least 55 years for Caucasians and at least 50 years for African Americans, because prostate cancer incidence rates for African Americans aged 50–55 are similar to those of Caucasians aged 55–60. Subjects will be randomly and equally distributed among four study arms (Figure 3). Intervention will consist of a daily oral dose of study medication and/or matched placebo according to the randomization. Study duration will be 12 years, with a 5-year uniform accrual period and an intervention period of between 7 and 12 years, depending on the time of randomization. Men will be followed annually with DRE and PSA, and the endpoint will be the incidence of clinically evident prostate cancer. Secondary endpoints will include prostate cancer–free survival, all-cause mortality, and the incidence and mortality rates of other cancers and diseases potentially affected by the chronic use of selenium and vitamin E. Other trial objectives will include periodic quality-of-life assessments, assessment of serum micronutrient levels and prostate cancer risk, and evaluation of biological and genetic markers for the risk of prostate cancer. Dietary Intervention Marked disparities in the worldwide incidence of prostate cancer have led to speculation that dietary influences may be important in tumor develop- Soy and Isoflavones Legumes are low in fat and rich in protein, dietary fiber, and a variety of micronutrients and phytochemicals.26 They play an important role in the traditional diets of Eastern countries where prostate cancer incidence is low, but only a minor role in the West where the incidence is highest worldwide. Soybeans are unique among the legumes because they are a concentrated source of isoflavones that have weak estrogenic activity. Genistein, the predominant isoflavone in soy, also appears to influence signal transduction. Epidemiologic observations dating to the early 1990s on the inverse relationship of soy intake and incidence of prostate cancer have stimulated research is this area. At least seven studies have demonstrated a consistent and statistically significant anticancer effect of soy-based diets compared with controls in a variety of prostate cancer animal-model systems. The results of At least seven studies have demonstrated a consistent and statistically significant anticancer effect of soy-based diets. ment. Abundant epidemiologic evidence exists to support this hypothesis, and there is widespread belief among established patients and those at risk that such supplementation is helpful. For example, of the more than 15,000 participants in the PCPT who completed food-frequency and dietary-supplement questionnaires, these studies are summarized in Table 8. Several anticarcinogens, including protease inhibitors, phytate, phytosterols, saponins, lignins, and isoflavones, have been identified in soybeans.27 These compounds exert their anticancer effects by a variety of hormonal and nonhormonal VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S23 CaP Prevention: Genetics, Chemoprevention, and Diet continued Table 8 Effects of Dietary Soy on Prostate Cancer Animal Models Author Dietary Source of Soy or Isoflavones Model System Findings Landstrom et al51 Soy flour Rat Dunning R3327 Inhibition of tumor growth Increased urinary excretion of isoflavones Zhou et al52 Soy protein or soy phytochemical concentrate LnCaP SCID mouse xenografts Reduced tumor volume Increased apoptotic index Decreased proliferation and microvessel density Bylund et al53 Soy protein LnCaP nude mouse xenografts Reduced tumor incidence and volume Lower PSA production Aronson et al54 Soy protein and isoflavone extract LnCaP SCID mouse xenografts Reduced tumor growth rate and volume Pollard et al55 Soy protein isolate Lobund–Wistar rat Reduced incidence of spontaneous tumors Lower serum testosterone Mentor-Marcel et al56 Genistein TRAMP Dose-dependent reduction in progression to poorly differentiated tumors Lamartiniere et al57 Genistein N-MNU induced and TRAMP Dose-dependent reduction in progression to poorly differentiated tumors SCID, severe combined-immunodeficient; N-MNU, N-methylnitrosourea; PSA, prostate-specific antigen. mechanisms. The hormonal effects of isoflavones and other phytoestrogens include both estrogenic activity and increased sex hormone binding–globulin. These effects reduce the serum concentration of testosterone, which could have a direct antiproliferative effect on the prostate. Genistein inhibits the growth of both androgendependent and androgen-independent prostate cancer cells in vitro.28 Other potential anticancer mechanisms for soy-based compounds include inhibition of cellular enzymes (including PSA), modulation of growth factors, and antiangiogenic effects. Findings from various studies are summarized in Table 9. After oral S24 VOL. 4 SUPPL. 5 2002 ingestion, isoflavones appear in prostatic secretions in concentrations several-fold higher than in serum.29 Concentrations of these agents in seminal fluid are highest in men from soy food–consuming countries. These observations suggest that the effects of isoflavones are exerted locally within the prostate. Epidemiologic evidence on soy. An early prospective study by Severson found that consumption of tofu was associated with a markedly reduced, but not quite statistically significant, risk of prostate cancer (relative risk = 0.35) in those who consumed tofu five times per week compared with those who ate it just REVIEWS IN UROLOGY once per week.30 Soon thereafter a group of Finnish researchers reported that Japanese men excrete high levels of isoflavones in the urine and that urinary levels correlated with soybean-product intake.31 In a follow-up study, the same investigators compared plasma levels of four isoflavonoids in 14 Japanese and 14 Finnish men. The mean plasma total isoflavonoid levels were 7 to 110 times higher in the Japanese men, and genistein occurred in the highest concentration.32 These observations sparked much interest because Finnish men have one of the highest worldwide mortality rates for prostate cancer. A larger study by Hebert CaP Prevention: Genetics, Chemoprevention, and Diet Table 9 Potential Anticancer Effects of Soy, Phytoestrogens, and Isoflavones Author Soy Component Mechanism Kim et al58 Genistein Modulates TGF-1 Davis et al59 Genistein Decreases NF- B DNA binding and activation Davis et al60 Genistein Inhibits PSA secretion Shen et al61 Genistein Induces G(1) cell-cycle block mediated by p27(KIP1) and p21(WAF1) Weber et al62 Phytoestrogens Reduced prostate weight in Sprague-Dawley rats No effect on SRDA2 Genistein Down-regulates AR and ER Rosenberg Zand et al Various flavenoids Blocks PSA production Fotsis et al Genistein Antiangiogenic Fritz et al63 64 65 TGF-1, tumor growth factor -1; PSA, prostate-specific antigen; SRDA2, steroid 5- reductase; AR, androgen receptor; ER, estrogen receptor. investigated predictive variables for prostate cancer mortality in data from 59 countries. Prostate cancer mortality was inversely associated with estimated consumption of cereals, nuts and oilseed, and fish. In the 42 countries for which relevant data were available, soy products were found to be protective, with an effect size per kilocalorie at least four times as large as that of any other dietary factor.33 Jacobsen reported a prospective study of 12,395 Seventh-Day Adventists in California. With 225 incident prostate cancers in the study cohort, consumption of soy milk more than once a day was associated with a 70% reduction in the risk of developing prostate cancer.34 Taken together, these epidemiologic observations support the hypothesis that soy and isoflavone consumption lowers the lifetime risk of developing or dying from prostate cancer. Clinical trials. No large-scale clinical trials using soy or soy-based products as preventative or therapeutic agents in prostate cancer have been reported. One study has demonstrated that healthy male subjects receiving 50 mg isoflavone mixture (Novasoy) twice daily for 3 weeks are protected from tumor necrosis factor (TNF)-–induced NF-B activation.35 In addition, a reduction of 5-hydroxymethyl-2'-deoxyuridine (5-OHmdU), a marker for oxidative DNA damage, was also observed following isoflavone supplementation. This preliminary study demonstrates that soy isoflavone supplementation may protect cells from oxidative-stress–inducing agents by inhibiting NF-B activation and decreasing DNA adduct levels. Ongoing trials. Three ongoing trials are examining the role of soy-based dietary supplementation as therapy for men in various clinical scenarios. Bosland is conducting two ongoing randomized, double-blind, placebocontrolled clinical trials with soy protein as intervention in men who, after definitive treatment for localized prostate cancer, show high risk of recurrence or of rising PSA.36 In the trial with men at high risk for recurrence, participants start intervention within 4 months after surgery and are followed for up to 2 years; primary endpoints are PSA failure rate and time to PSA failure. In the trial with men with PSA failure (PSA 0.1–2.0 ng/mL), participants receive treatment for 8 months and the primary endpoint is rise in PSA over time. No results have yet been reported. Ornish is conducting a randomized, prospective clinical trial on men with clinically localized prostate cancer who have selected “watchful waiting" as primary therapy. Since its inception in April 1997, 93 men have been randomized to control (n = 47) or dietary and lifestyle intervention (n = 46). Patients in the intervention group are asked to eat a low-fat, soy-supplemented vegan diet and take part in stress management, psychosocial group support, and exercise programs. After 1 year, adherence to all four interventions was greater than 80%, and no deaths or adverse outcomes have occurred. No results on PSA patterns or disease progression have yet been reported.37 Lycopene Lycopene is a red-orange carotenoid found primarily in tomatoes and tomato-derived products, including tomato sauce, tomato paste, and ketchup, and other red fruits and vegetables, including pink grapefruit, apricots, watermelon, and guava. Lycopene is a highly unsaturated acyclic isomer of -carotene, is the predominant carotenoid in human plasma, and possesses potent antioxidant activity.38,39 Lycopene is concentrated in the liver, adrenal, and testis, and is the predominant carotenoid in the human prostate. Kotake-Nara studied the in vitro VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S25 CaP Prevention: Genetics, Chemoprevention, and Diet continued effects of various carotenoids including lycopene on the growth of three prostate cancer cell lines, PC-3, DU 145, and LNCaP.40 When the prostate cancer cells were cultured in a carotenoid-supplemented medium for 72 hours at 20 mol/L, 5,6-monoepoxy carotenoids, namely, neoxanthin from spinach and fucoxanthin from brown algae, significantly reduced cell viability to, respectively, 10.9% and 14.9% for PC-3, 15.0% and 5.0% for DU 145, and nearly 0% and 9.8% for LNCaP. Acyclic carotenoids such as phytofluene, zeta-carotene, and lycopene, all of which are present in tomatoes, also significantly reduced cell viability. Pastori demonstrated that lycopene exhibited synergistic antiproliferative effects in combination with -tocopherol on DU-145 and PC-3 benzo[a]pyrene-induced prostate tumors in the lacZ mouse.44 The most important anticancer activity of lycopene may be its antioxidant capacity, which is the strongest among all carotenoid species. However, lycopene also possesses other biological activities that may be important (Table 10). Unlike other carotenoids, lycopene does not form vitamin A and has no vitamin A–linked activity. Epidemiologic/population evidence. Many epidemiological studies with various designs have examined the association of lycopene intake, serum and tissue lycopene levels, and prostate cancer risk. Although not all studies have shown a positive correlation between lycopene intake and levels, the collected evidence The most important anticancer activity of lycopene may be its antioxidant capacity, which is the strongest among all carotenoid species. cells.41 Lycopene is found at physiologically significant levels in the rat prostate after oral ingestion,42 but does not inhibit 3,2'-dimethyl-4aminobiphenol (DMAB)– or 2-amino1-methylimidazo[4,5-b]pyridine (PhIP)–induced rat ventral prostate cancer43 or spontaneous and does suggest a protective effect of lycopene on the risk of developing prostate cancer. In a review of the epidemiologic evidence for all cancers, Giovannucci summarized 72 studies and concluded that 57 showed a reduced risk of cancer in men with highest tomato intake.45 Summarizing Table 10 Potential Anticancer Mechanisms of Lycopene Antioxidant Activity39,66 Nonoxidative activity Regulation of cell-cell communication67 Suppression of protein phosphorylation68 Modulation of cytochrome P45069 Inhibition of IGF-1 signaling70 Immunomodulation71 IGF-1, insulin-like growth factor-1. the data specific to prostate cancer, he reported that six studies showed that high dietary intake of tomatoes or lycopene was associated with a 30%–40% reduction in prostate cancer risk, three showed a similar risk reduction but were not statistically significant, and seven did not support an association.45 Rao demonstrated in a case-control study that serum and tissue lycopene levels were significantly lower in prostate cancer patients, with no observed differences in other carotenoids between the two groups.46 Lu studied serum carotenoid levels in 65 patients with prostate cancer and 132 cancer-free controls.47 After adjusting for age, race, years of education, daily caloric intake, packyears of smoking, alcohol consump- Main Points • The substantial morbidity and mortality of prostate cancer make primary prevention an important goal. • Two developments in the study of prostate cancer may make the goal of primary prevention a reality in the near future: the identification of susceptibility genes and the identification of potentially anticarcinogenic dietary influences and pharmacologic agents. • Individuals identified as at risk through simple genetic screening could undergo a modified screening schedule, be entered into clinical trials of chemoprevention or dietary modification, and/or be treated according to the clinical characteristics of the cancer associated with a particular gene. • Several large chemoprevention trials are under way to investigate the effects of substances such as finasteride, selenium, and vitamin E in the prevention of prostate cancer. • Dietary substances such as soy and lycopene are also being studied for their potential anti-cancer benefits. S26 VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY CaP Prevention: Genetics, Chemoprevention, and Diet tion, and family history of prostate cancer, significantly inverse associations with prostate cancer were observed with plasma concentrations of lycopene (OR = 0.17) and zeaxanthin (OR = 0.22) when comparing the highest with the lowest quartiles. In a follow-up of a prospective study based on a single dietary questionnaire, Giovannucci conducted a large prospective study of risk reduction and lycopene intake using multiple questionnaires over a 12-year period.48 Among a cohort of 47,365 men in the Health Professionals Follow-up Study, 2481 incident prostate cancer cases were observed between 1986 and 1998. High lycopene intake was associated with a statistically significant reduction in risk of prostate cancer of 16% (RR = 0.84 for highest vs lowest quintile of intake); high tomato sauce intake was associated with a statistically significant risk reduction of 23% (RR = 0.77, 2+ servings/wk vs <1 serving/mo). The observations held even when controlling for potential confounders, including overall fruit and vegetable intake, Mediterranean diet, prevalence of PSA screening, and ethnicity. Clinical trials. Two non–placebocontrolled, prospective clinical trials examining the effect of lycopene on known prostate cancer have been reported.49,50 In the first trial, 26 men with clinically localized prostate cancer scheduled for radical prostatectomy were randomized to a preoperative regimen of either 15 mg lycopene orally twice a day for 3 weeks or no lycopene. Serum PSA levels decreased by 18% in the lycopene group and increased by 14% in the control group. A statistically significant difference was observed in the rate of positive margins in the lycopene versus control groups (17% vs 72%, respectively). No differences were seen in various biological endpoints including tumor expression of bcl-2, bax, or connexin 43. The study is limited by a small sample size and significant differences in tumor burden between the intervention and control groups as assessed by pretreatment stage and tumor grade, which could account for the differences in pathological findings. In the second trial, 32 patients with localized disease scheduled for radical prostatectomy ate tomato sauce–based pasta dishes (equal to 30 mg of lycopene per day) for the 3 weeks before surgery. Serum and prostate lycopene concentrations were statistically significantly increased in the intervention group. Compared with preintervention levels, both leukocyte and prostate oxidative DNA damage were also significantly reduced after intervention. A small but statistically significant reduction in serum PSA was also observed (from 10.9 ng/mL to 8.7 ng/mL). Together these clinical trials support the hypothesis that lycopene is active against prostate cancer and that additional larger studies with appropriate controls are indicated. for the development of prostate cancer are currently under way or about to open. The future of prostate cancer is in the genes and our ability to manipulate the molecular events they cause. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Conclusion At least five susceptibility loci for the development of prostate cancer have been identified in the last several years. While the specific genes involved have yet to be fully characterized, these discoveries hold promise for the identification of individuals at risk for prostate cancer years before development of the disease. Individuals identified by simple genetic screening (ie, a test on peripheral blood) could have a modified screening schedule, be entered into clinical trials of chemoprevention or dietary modification, and/or be treated according to the clinical characteristics of the cancer associated with a particular gene. Several large chemoprevention trials that exploit underlying pathogenetic mechanisms 11. 12. 13. 14. 15. 16. 17. 18. Ries LAG, Kosary CL, Hankey BF, et al, eds. SEER Cancer Statistics Review, 1973-1995. Bethesda, MD: National Cancer Institute; 1998. Catalona WJ, Smith D, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991;324:1156–1161. Chodak GW, Thompson IM, Gerber GS, et al. Results from two prostate cancer screening programs. JAMA. In press. Mishina T, Watanabe H, Araki H, et al. Epidemiological study of prostatic cancer by matched-pair analysis. Prostate. 1985;6:423–436. Bratt O. Hereditary prostate cancer. Br J Urol Int. 2000;85:588–598. Smith J, Freije D, Carpten J, et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science. 1996;274:1371–1374. Carpten J, Nupponen N, Isaacs S, et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet. 2002;30:181–184. Rebbeck TR, Walker AH, Zeigler-Johnson C, et al. Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet. 2000;67:1014–1019. Tavtigian SV, Simard J, Teng DH, et al. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet. 2001;27:172–180. Wu YQ, Chen H, Rubin MA, et al. Loss of heterozygosity of the putative prostate cancer susceptibility gene HPC2/ELAC2 is uncommon in sporadic and familial prostate cancer. Cancer Res. 2001;61:8651–8653. Suarez BK, Gerhard DS, Lin J, et al. Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer Res. 2001;61:4982–4984. Berthon P, Valeri A, Cohen-Akenine A, et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet. 1998;62:1416–1424. Xu J, Meyers D, Freije D, et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet. 1998;20:175–179. Gibbs M, Stanford J, McIndoe R, et al. Evidence for a rare prostate cancer susceptibility locus at chromosome 1p36. Am J Hum Genet. 1999;64:776–787. Paris PL, Witte JS, Kupelian PA, et al. Prostate cancer suppressor gene locus on chromosome 16q23.2 that corresponds to a prostate cancer susceptibility locus. Cancer Research. In press. Kupelian P, Kupelian V, Witte J, et al. Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome. J Clin Oncol. 1997;15:1478–1480. Kupelian P, Klein E, Witte J, et al. Familial prostate cancer: a different disease? J Urol. 1997;158:2197–2201. Rodriguez C, Calle EE, Tatham LM, et al. Family history of breast cancer as a predictor for fatal VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S27 CaP Prevention: Genetics, Chemoprevention, and Diet continued 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. S28 prostate cancer. Epidemiology. 1998;9:525–529. Russell DW, Wilson JD. Steroid 5-alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25–61. Thompson IM, Coltman CA Jr, Crowley J. Chemoprevention of prostate cancer: The Prostate Cancer Prevention Trial. Prostate. 1997;33:217–221. 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. Clark LC, Combs GF Jr, Turnbull BW, et al, for the Nutritional Prevention of Cancer Study Group. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. JAMA. 1996;276:1957–1963. Heinonen OP, Albanes D, Huttunen JK, et al. Prostate cancer and supplementation with -tocopherol and ß-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440–446. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. J Urol. 2001;166:1311–1315. Neuhouser ML, Kristal AR, Patterson RE, et al. Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials. Nutr Cancer. 2001;39:12–18. Messina MJ. Legumes and soybeans: overview of their nutritional profiles and health effects. Am J Clin Nutr. 1999;70(suppl 3):439S–450S. Kumar NB, Besterman-Dahan K. Nutrients in the chemoprevention of prostate cancer: current and future prospects. Cancer Control. 1999;6:580–586. Santibáñez JF, Navarro A, Martinez J. Genistein inhibits proliferation and in vitro invasive potential of human prostatic cancer cell lines. Anticancer Res. 1997;17:1199–1204. Morton MS, Matos-Ferreira A, AbranchesMonteiro L, et al. Measurement and metabolism of isoflavonoids and lignans in human male. Cancer Lett. 1997;114:145–151. Severson KJ, 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. Adlercreutz H, Honjo H, Higashi A, et al. Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet. Am J Clin Nutr. 1991;54:1093–1100. Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet. 1993;342:1209–1210. Hebert JR, Hurley TG, Olendzki BC, et al. Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J Natl Cancer Inst. 1998;90:1637–1647. 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. Davis JN, Kucuk O, Djuric Z, Sarkar FH. Soy isoflavone supplementation in healthy men prevents NF-kappaB activation by TNF-alpha in blood lymphocytes. Free Radic Biol Med. 2001;30:1293–1302 Bosland MC, Kato I, Melamed J, et al. Chemoprevention trials in men with prostatespecific antigen failure or at high risk for recurrence after radical prostatectomy: application VOL. 4 SUPPL. 5 2002 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. REVIEWS IN UROLOGY to efficacy assessment of soy protein. Urology. 2001;57(suppl 4, pt 1):202–204 Ornish DM, Lee KL, Fair WR, et al. Dietary trial in prostate cancer: early experience and implications for clinical trial design. Urology. 2001;57(4 Suppl 4, pt 1):200–201. Agarwal S, Rao AV. Tomato lycopene and its role in human health and chronic diseases. CMAJ. 2000;163:739–744. Woodall AA, Lee SWM, Weesie RJ, et al. Oxidation of carotenoids by free radicals: relationship between structure and reactivity. Biochim Biophys Acta. 1997;1336:33–42. Kotake-Nara E, Kushiro M, Zhang H, et al. Carotenoids affect proliferation of human prostate cancer cells. J Nutr. 2001;131:3303–3306. Pastori M, Pfander H, Boscoboinik D, Azzi A. Lycopene in association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells. Biochem Biophys Res Commun. 1998;250:582–585. Zhao Z, Khachik F, Richie JP Jr, Cohen LA. Lycopene uptake and tissue disposition in male and female rats. Proc Soc Exp Biol Med. 1998;218:109–114. Imaida K, Tamano S, Kato K, et al. Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis. Carcinogenesis. 2001;22:467–472. Guttenplan JB, Chen M, Kosinska W, et al. Effects of a lycopene-rich diet on spontaneous and benzo[a]pyrene-induced mutagenesis in the prostate, lung, and colon in the lacZ mouse. Cancer Lett. 2001;164:1–6. Giovannucci E, Clinton SK. Tomatoes, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317–331. Rao AV, Fleshner N, Agarwal S. Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study. Nutr Cancer. 1999;33:159–164. Lu QY, Hung JC, Heber D, et al. Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Cancer Epidemiol Biomarkers Prev. 2001;10:749–756. Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002;94:391–398. Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev. 2001;10:861–868. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst. 2001;93:1872–1879 Landstrom M, Zhang JX, Hallmans G, et al. Inhibitory effects of soy and rye diets on the development of Dunning R3327 prostate adenocarcinoma in rats. Prostate. 1998;36:151–161 Zhou JR, Gugger ET, Tanaka T, et al. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr. 1999;129:1628–1635. Bylund A, Zhang JX, Bergh A, et al. Rye bran and soy protein delay growth and increase apoptosis of human LNCaP prostate adenocarcinoma in nude mice. Prostate. 2000;42:304–314. Aronson WJ, Tymchuk CN, Elashoff RM, et al. Decreased growth of human prostate LNCaP tumors in SCID mice fed a low-fat, soy protein diet with isoflavones. Nutr Cancer. 1999;35:130–136. 55. Pollard M, Wolter W. Prevention of spontaneous prostate-related cancer in Lobund-Wistar rats by a soy protein isolate/isoflavone diet. Prostate. 2000;45:101–105. 56. Mentor-Marcel R, Lamartiniere CA, Eltoum IE, et al. Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP). Cancer Res. 2001;61:6777–6782. 57. Lamartiniere CA, Cotroneo MS, Fritz WA, et al. Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr. 2002;132:552S–558S. 58. Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. Am J Clin Nutr. 1998;68(suppl 6):1418S–1425S. 59. Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-kappa B activation in prostate cancer cells. Nutr Cancer. 1999;35:167–174. 60. Davis JN, Muqim N, Bhuiyan M, et al. Inhibition of prostate specific antigen expression by genistein in prostate cancer cells. Int J Oncol. 2000;16:1091–1097. 61. Shen JC, Klein RD, Wei Q, et al. Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. Mol Carcinog. 2000;29:92–102. 62. Weber KS, Setchell KD, Stocco DM, Lephart ED. Dietary soy-phytoestrogens decrease testosterone levels and prostate weight without altering LH, prostate 5alpha-reductase or testicular steroidogenic acute regulatory peptide levels in adult male Sprague-Dawley rats. J Endocrinol. 2001;170:591–599. 63. Fritz WA, Wang J, Eltoum IE, Lamartiniere CA. Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate. Mol Cell Endocrinol. 2002;186:89–99. 64. Rosenberg Zand RS, Jenkins DJ, Brown TJ, Diamandis EP. Flavonoids can block PSA production by breast and prostate cancer cell lines. Clin Chim Acta. 2002;317:17–26. 65. Fotsis T, Pepper M, Aldercruetz H. Genistein, a dietary-dervied inhibitor of in-vitro angiogenesis. Proc Natl Acad Sci USA. 1993;90:2690–2694. 66. Sies H, Stahl W. Vitamins E and C, b-carotene, and other carotenoids as antioxidants. Am J Clin Nutr. 1995;62(suppl 6):1315S–1321S. 67. Zhang LX, Cooney RV, Bertram JS. Carotenoids upregulate connexin43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res. 1992;52:5707–5712. 68. Matsushima NR, Shidoji Y, Nishiwaki S, et al. Suppression by carotenoids of microcystininduced morphological changes in mouse hepatocytes. Lipids. 1995;30:1029–1034. 69. Astorg P, Gradelet S, Berges R, Suschetet M. Dietary lycopene decreases the initiation of liver perineoplastic foci by diethylnitrosamine in the rat. Nutr Cancer. 1997;29:60–68. 70. Karas M, Amir H, Fishman D, et al. Lycopene interferes with cell cycle progression and insulinlike growth factor I signaling in mammary cancer cells. Nutr Cancer. 2000;36:101–111. 71. Kobayashi T, Iijima K, Mitamura T, et al. Effects of lycopene, a carotenoid, on intrathymic T cell differentiation and peripheral CD4/CD8 ration in a high mammary tumor strain of SHN retired mice. Anticancer Drugs. 1996;7:195–198.