Hormonal Prevention
Dietary Prevention With Fruit, Vegetables, and a Low-Fat Diet
Chemoprevention
        Chemoprevention with vitamin E (alpha-tocopherol)
        Chemoprevention with selenium
        Chemoprevention with lycopene

Hormonal Prevention

The Prostate Cancer Prevention Trial, a large randomized placebo-controlled trial of finasteride (an inhibitor of alpha-reductase), was performed in 18,882 men aged 55 years or older. At 7 years, the incidence of prostate cancer was 18.4% in the finasteride group versus 24.4% in the placebo group, a relative risk reduction of 24.8% (95% confidence interval [CI], 18.6%–30.6%; P < .001). The finasteride group had more patients with Gleason grade 7 to 10, but the clinical significance of Gleason scoring is uncertain in conditions of androgen deprivation.[1] High-grade cancers were noted in 6.4% of finasteride patients, compared with 5.1% of men receiving a placebo. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase over time.[2]

Finasteride decreases the risk of prostate cancer but may also alter the detection of disease through effects on prostate-specific antigen (PSA) and decreased prostate volume (24%), creating a detection bias.[3] In men receiving finasteride, varying adjustment factors may be needed to determine whether PSA is in the normal range.[4] There may be an artifactual histological effect of finasteride on Gleason scoring.

It is possible that finasteride induced the development of high-grade epithelial neoplasia, but this has not been demonstrated.[3] With a finasteride-induced development of high-grade prostate cancer, a gradual and progressive increase in the number of high-grade tumors would have been expected over the 7 years, compared with placebo; however, this was not the case. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase over time.[2]

In general, agents that are used for hormonal therapy of existing prostate cancers would be unsuitable for prostate cancer chemoprevention because of the cost and wide variety of side effects including sexual dysfunction, osteoporosis, and vasomotor symptoms (hot flushes).[5] Newer antiandrogens may play a role as preventive agents in the future.[6]

Results from studies of the association between dietary intake of fruits and vegetables and risk of prostate cancer are not consistent. A study evaluated 1,619 prostate cancer cases and 1,618 controls in a multicenter, multiethnic population. The study found that intake of legumes and yellow-orange and cruciferous vegetables was associated with a lower risk of prostate cancer.[7]

The European Prospective Investigation into Cancer and Nutrition examined the association between fruit and vegetable intake and subsequent prostate cancer. After an average follow-up of 4.8 years, 1,104 men developed prostate cancer among the 130,544 male participants. No statistically significant associations were observed for fruit intake, vegetable intake, cruciferous vegetable intake, or the intake of fruits and vegetables combined.[8]

One study of dietary intervention over a 4-year period with reduced fat and increased consumption of fruit, vegetables, and fiber had no impact on serum PSA levels.[9] It is unknown whether dietary modification through the use of a low-fat, plant-based diet will reduce prostate cancer risk. While this outcome is unknown, multiple additional benefits may be gleaned by such a diet, to include a lower risk of hyperlipidemia, better control of blood pressure, and a lower risk of cardiovascular disease—all of which may merit adoption of such a diet.

Several agents, including alpha-tocopherol, selenium, lycopene, difluoromethylornithine,[10-14] vitamin D,[15-17] and isoflavonoids,[18,19] have shown potential in either clinical or laboratory studies for chemoprevention of prostate cancer. Based mainly on clinical trial results, alpha-tocopherol, selenium, and lycopene are receiving the greatest public health interest and are highlighted in the chemoprevention discussions below.

In 1986, while studying the effect of adriamycin on the human prostatic cancer cell line DU-145, it was also found that alpha-tocopherol may have a possible effect.[20] The study, employing d-alpha-tocopheryl acid succinate, found that not only did it enhance the cytotoxic effect of adriamycin, but it also inhibited cell growth when used alone. This inhibition was dose-dependent. Finally, these properties were noted at doses that are routinely attained in plasma.[21] These same doses have been demonstrated to have no effect on normal mouse fibroblasts.[22,23] In a similar study using the Nb rat prostate adenocarcinoma model, the combination of adriamycin-vitamin E resulted in a lower average final tumor volume when compared with control animals.[24]

A nested case-control study of serum micronutrients from a cohort of 6,860 Japanese-American men analyzed 142 confirmed cases of prostate cancer and compared the cases with a similar number of controls.[25] Although the difference did not reach statistical significance, the odds ratio for gamma-tocopherol was 0.7 (95% CI, 0.3–1.5). In a study of 2,974 male workers in Basel, Switzerland, low levels of lipid-adjusted plasma of vitamin E were associated with a statistically significant increased risk for lung cancer.[26] Additionally, male smokers who had low levels of vitamin E were associated with a higher risk of prostate cancer.

The effect of the RRR-alpha-tocopheryl succinate derivative of vitamin E (vitamin E succinate [VES]) on three metastatic human prostate cancer cell lines was studied: LNCaP, PC-3, and DU-145.[27] It was found that VES inhibited cell growth and deoxyribonucleic acid (DNA) synthesis in all cell lines in a dose-dependent manner. In a similar manner, the effect of dl-alpha-tocopherol in CRL-1740 prostate cancer cells was studied.[28] Even at 0.1 mM vitamin E, the prostate cancer cell line demonstrated growth suppression. When studying tritiated thymidine incorporation in the prostate cell line, it was found that vitamin E supplementation reduced DNA synthesis. Additionally, analysis of high-molecular weight DNA indicated that apoptotic changes were ongoing and may have been caused by vitamin E supplementation.

Not all studies of alpha-tocopherol have found the agents to be effective. Using the 3,2'-dimethyl-4-aminobiphenyl initiated rate prostate cancer model in F344 rats, the effect of six naturally occurring antioxidants on carcinogenesis was studied.[29] Using dietary 2 ppm selenium and 1% alpha-tocopherol, no differences were noted in atypical hyperplasia or carcinoma rates in the study groups compared with control animals. In a large nested case-control study, serum obtained in 1974 from 25,802 persons in Washington County, Maryland was studied.[30] Serum levels of tocopherol were compared between 103 men who developed prostate cancer during 13 years of follow-up to 103 control patients matched for age and race. No association was found between tocopherol levels and cancer risk.

The largest assessment of the impact of alpha-tocopherol on prostate cancer risk came from the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study. This prostate cancer analysis was secondary to the ATBC study’s primary objective of assessing whether alpha-tocopherol and/or beta carotene could reduce the incidence of lung cancer in male smokers.[31] The ATBC study was prompted by multiple observations that populations with higher intakes of diets rich in alpha-tocopherol and beta carotene had a lower risk of cancer.[32,33] Conducted in 14 geographic areas in southwestern Finland, the ATBC study was a randomized, double-blind, placebo-controlled comparison of alpha-tocopherol and beta carotene. The study employed a 2 x 2 factorial design, and each participant received two capsules. Specifically, participants were divided into four similar study arms/groups: one receiving beta carotene and placebo, one receiving alpha-tocopherol and placebo, one receiving both active agents, and one receiving two placebo capsules. The form of alpha-tocopherol in this study was dl-alpha tocopherol acetate. A total of 29,133 men were enrolled. The daily doses of alpha-tocopherol and beta carotene were 50 mg and 20 mg, respectively. Median follow-up was 6.1 years (based on a total of 169,751 man-years). Mean patient age was 57.2 years. Cancers in participants were identified through the Finnish Cancer Registry.

In their 1994 report,[20] the ATBC study authors concluded that 5 to 8 years of dietary supplementation with alpha-tocopherol produced no reduction and with beta carotene produced a statistically significant increase in lung cancer incidence in male smokers. A secondary analysis revealed that there were substantially fewer prostate cancers in participants who were randomly assigned to receive alpha-tocopherol (99 prostate cancers) than in those who were not randomly assigned to receive alpha-tocopherol (151 prostate cancers). These results translate into an incidence of 11.7 cases per 10,000 person-years (with alpha-tocopherol) versus an incidence of 17.8 cases per 10,000 person-years (without alpha-tocopherol).

Recognizing that the data from the ATBC study may only apply to smokers, another study analyzed self-reported vitamin E use in smokers and nonsmokers in the Health Professionals Follow-up Study.[34] While in smokers and men who had quit smoking the risk of metastatic or fatal prostate cancer was lower among men who consumed at least 100 IU of vitamin E daily, no difference in prostate cancer was seen in nonsmokers.

Two clinical trials conducted in Linxian, China,[35,36] also tested alpha-tocopherol, along with selenium (discussed below) and various other agents, in humans. The Linxian general population trial involved approximately 30,000 patients and had a very complicated factorial design involving various combinations of vitamins and minerals primarily to reduce the incidence and/or mortality of all cancers (not necessarily prostate cancer). Although the trial was not positive in respect to its primary objectives, secondary analyses indicated that one combination, which included selenium (50 µg/day in a yeast supplement), alpha-tocopherol (30 mg/day), and beta carotene (15 mg/day), was associated with a statistically significantly lower total-mortality rate, a statistically nonsignificant 13% reduction in the all-cancer mortality rate, and a statistically significant lower gastric cancer (cardia plus noncardia) mortality rate (a major cancer in Linxian). A second, smaller Linxian trial (with approximately 3,300 patients) tested a combination of these three agents with several additional vitamins and minerals (versus placebo) in preventing esophageal/gastric cardia cancer in patients with esophageal dysplasia. The treatment arm did not reduce the cancer risk, and a statistically nonsignificant 18% increase in overall gastric (cardia and noncardia) cancer mortality occurred. Prostate cancer mortality was not reported. It is difficult to compare results of the two Linxian trials, however, because the trials differed in scale, patient characteristics, and study agents (additional agents in the latter trial may have affected the activity of selenium, alpha-tocopherol, and beta carotene indicated in the former trial). It is difficult to know how either trial would apply to the United States, with a very different (generally far lower) risk in the general population.

Selenium is an essential trace element in humans and other species.[37-39] A substantial volume of data suggests that supplementation with selenium reduces the risk of a variety of cancers in chemically induced cancers,[40-58] in spontaneous animal tumors,[59] and in transplanted animal tumor lines.[60] Studies of geographical areas with varying dietary selenium content have demonstrated an inverse relationship between selenium intake and cancer risk.[61,62] Similarly, in a study of environmental selenium levels (forage crop concentrations of selenium), an inverse relationship was again noted.[63] Epidemiologic studies have had mixed results with statistically significant (inverse) relationships encountered in some studies [64-79] while others have not encountered a statistically higher risk in patients with low selenium levels or a low selenium intake.[80-88]

In a case-control study, serum samples collected in 1973 from 111 patients who developed cancer during the subsequent 5 years were studied and compared with serum samples from 210 cancer-free people matched for age, race, sex, and smoking history.[66] Study participants were obtained from a cohort of 10,940 men enrolled in the Hypertension Detection Follow-up Programme. Mean serum selenium level was lower in cancer cases (0.129 ± standard error of the mean [SEM] 0.002 µg/mL) than in controls (0.136 ± SEM 0.002 µg/mL). The association between low selenium level and cancer was strongest for gastrointestinal and prostate cancer.

The mechanism of action of selenium is not clear, but there are a number of hypotheses. In cell cultures, it reduces the effect of a number of described mutagens [89-93] and may alter the metabolism of other carcinogens.[94-98] A variety of other potential actions that have been suggested include effects on the immune and endocrine systems, production of cytotoxic selenium metabolites, initiation of apoptosis, inhibition of protein synthesis, protection against the action of free radicals and oxidative damage through the action of selenium as an antioxidant as it is incorporated into glutathione peroxidase, as well as inhibition of specific enzymes.[31,99-102]

A multi-institutional study designed to prevent skin cancer randomly assigned a group of 1,312 patients with a history of basal cell or squamous cell carcinoma of the skin to either 200 µg selenium per day (as selenized yeast) or placebo (nonselenized yeast).[103] Although the study began in 1983, additional funding subsequently allowed the ascertainment of rates of other cancers in the two study groups. Baseline serum-PSA levels in both arms were also evaluated. This evaluation indicated that 12.4% of the selenium and 10.2% of the placebo group had prestudy serum PSAs greater than 4.0 ng/mL. After enrollment, plasma-selenium concentrations increased by approximately 67% in the selenium-treated patients. After an average follow-up of 6.4 years, cancer incidence rates were tabulated for both groups. The table below lists the various tumors studied, numbers of tumors in the two study arms, hazard ratio, and P values, which were derived from the Cox proportional hazard model, adjusted for age, sex, and smoking status at randomization. Selenium-treated patients experienced only about one-third as many prostate tumors as did patients receiving placebo. No patient experienced toxicity caused by selenosis, a side effect that has been reported in association with chronic feeding of inorganic and certain organic forms of selenium at levels greater than 5 ppm.[104] Only those participants with baseline plasma-selenium concentrations in the lowest two tertiles (<123.2 ng/mL) had statistically significant reductions in prostate cancer incidence. A statistically significant interaction between baseline plasma selenium and treatment was detected.[105]

Because preliminary data suggest that both selenium and vitamin E may reduce the risk of prostate cancer, a large randomized, prospective, double-blind study has been designed to determine whether selenium and vitamin E can reduce the risk of prostate cancer among healthy men. Enrollment for the Selenium and Vitamin E Cancer Prevention Trial (SELECT) began in 2001 [106] and completed accrual in 2004. More than 35,000 men have been enrolled and will be on study for at least 7 years. Final results are anticipated in 2013.[107]

Other clinical trials of selenium in humans include the two studies conducted in Linxian, China [35,36] that are discussed in the Chemoprevention with Vitamin E (Alpha-Tocopherol) section.

Evidence exists that a diet with a high intake of fruits and vegetables is associated with a lower risk of cancer. Which, if any, micronutrients may account for this reduction is unknown. One group of nutrients often postulated as having chemoprevention properties is the carotenoids. Lycopene is the predominant circulating carotenoid in Americans and has a number of potential activities, including an antioxidant effect.[108] It is encountered in a number of vegetables, most notably tomatoes, and is best absorbed if these products are cooked and in the presence of dietary fats or oils.

The earliest studies of the association of lycopene and prostate cancer risk were generally negative before 1995 with only one study of 180 case-control patients showing a reduced risk.[30,109-111] In 1995, an analysis of the Physicians’ Health Study found a one-third reduction in prostate cancer risk in the group of men with the highest consumption of tomato products when compared with the group with the lowest level of consumption, which was attributed to the lycopene content of these vegetables.[112] This large analysis prompted several subsequent studies, the results of which were mixed.[113,114] A review of the published data concluded that the evidence is weak that lycopene is associated with a reduced risk because previous studies were not controlled for total vegetable intake (i.e., separating the effect of tomatoes from vegetables), dietary intake instruments are poorly able to quantify lycopene intake, and other potential biases.[115] Specific dietary supplementation with lycopene remains to be demonstrated to reduce prostate cancer risk.

References

1. Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349 (3): 215-24, 2003.  [PUBMED Abstract]
   
   
2. Thompson IM, Klein EA, Lippman SM, et al.: Prevention of prostate cancer with finasteride: US/European perspective. Eur Urol 44 (6): 650-5, 2003.  [PUBMED Abstract]
   
   
3. Andriole G, Bostwick D, Civantos F, et al.: The effects of 5alpha-reductase inhibitors on the natural history, detection and grading of prostate cancer: current state of knowledge. J Urol 174 (6): 2098-104, 2005.  [PUBMED Abstract]
   
   
4. Etzioni RD, Howlader N, Shaw PA, et al.: Long-term effects of finasteride on prostate specific antigen levels: results from the prostate cancer prevention trial. J Urol 174 (3): 877-81, 2005.  [PUBMED Abstract]
   
   
5. Thompson I, Feigl P, Coltman C: Chemoprevention of prostate cancer with finasteride. Important Adv Oncol : 57-76, 1995.  [PUBMED Abstract]
   
   
6. Nelson PS, Gleason TP, Brawer MK: Chemoprevention for prostatic intraepithelial neoplasia. Eur Urol 30 (2): 269-78, 1996.  [PUBMED Abstract]
   
   
7. Kolonel LN, Hankin JH, Whittemore AS, et al.: Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiol Biomarkers Prev 9 (8): 795-804, 2000.  [PUBMED Abstract]
   
   
8. Key TJ, Allen N, Appleby P, et al.: Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 109 (1): 119-24, 2004 Mar10.  [PUBMED Abstract]
   
   
9. Shike M, Latkany L, Riedel E, et al.: Lack of effect of a low-fat, high-fruit, -vegetable, and -fiber diet on serum prostate-specific antigen of men without prostate cancer: results from a randomized trial. J Clin Oncol 20 (17): 3592-8, 2002.  [PUBMED Abstract]
   
   
10. Heby O: Role of polyamines in the control of cell proliferation and differentiation. Differentiation 19 (1): 1-20, 1981.  [PUBMED Abstract]
    
    
11. Danzin C, Jung MJ, Grove J, et al.: Effect of alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on polyamine levels in rat tissues. Life Sci 24 (6): 519-24, 1979.  [PUBMED Abstract]
    
    
12. Metcalf BW, Bey P, Danzin C, et al.: Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C. 4.1.1.17) by substrate and product analogues. J Am Chem Soc 100(8): 2551-2553, 1978. 
    
    
13. Heston WD, Kadmon D, Lazan DW, et al.: Copenhagen rat prostatic tumor ornithine decarboxylase activity (ODC) and the effect of the ODC inhibitor alpha-difluoromethylornithine. Prostate 3 (4): 383-9, 1982.  [PUBMED Abstract]
    
    
14. Abeloff MD, Slavik M, Luk GD, et al.: Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis. J Clin Oncol 2 (2): 124-30, 1984.  [PUBMED Abstract]
    
    
15. Schwartz GG, Hulka BS: Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). Anticancer Res 10 (5A): 1307-11, 1990 Sep-Oct.  [PUBMED Abstract]
    
    
16. Eisman JA, Barkla DH, Tutton PJ: Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res 47 (1): 21-5, 1987.  [PUBMED Abstract]
    
    
17. Chida K, Hashiba H, Fukushima M, et al.: Inhibition of tumor promotion in mouse skin by 1 alpha,25-dihydroxyvitamin D3. Cancer Res 45 (11 Pt 1): 5426-30, 1985.  [PUBMED Abstract]
    
    
18. Adlercreutz H, Markkanen H, Watanabe S: Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342 (8881): 1209-10, 1993.  [PUBMED Abstract]
    
    
19. Peterson G, Barnes S: Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 22 (4): 335-45, 1993.  [PUBMED Abstract]
    
    
20. Ripoll EA, Rama BN, Webber MM: Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro. J Urol 136 (2): 529-31, 1986.  [PUBMED Abstract]
    
    
21. Gilbert HS, Stump DD, Ginsberg H, et al.: The effect of chronic hypocholesterolemia in myeloproliferative disease on the distribution of plasma and erythrocyte tocopherol. Am J Clin Nutr 40 (1): 95-100, 1984.  [PUBMED Abstract]
    
    
22. Prasad KN, Edwards-Prasad J: Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Res 42 (2): 550-5, 1982.  [PUBMED Abstract]
    
    
23. Landolph JR, Bhatt RS, Telfer N, et al.: Comparison of adriamycin- and ouabain-induced cytotoxicity and inhibition of 86rubidium transport in wild-type and ouabain-resistant C3H/10T1/2 mouse fibroblasts. Cancer Res 40 (12): 4581-8, 1980.  [PUBMED Abstract]
    
    
24. Nesbitt JA, Smith J, McDowell G, et al.: Adriamycin-vitamin E combination therapy for treatment of prostate adenocarcinoma in the Nb rat model. J Surg Oncol 38 (4): 283-4, 1988.  [PUBMED Abstract]
    
    
25. Nomura AM, Stemmermann GN, Lee J, et al.: Serum micronutrients and prostate cancer in Japanese Americans in Hawaii. Cancer Epidemiol Biomarkers Prev 6 (7): 487-91, 1997.  [PUBMED Abstract]
    
    
26. Eichholzer M, Stähelin HB, Gey KF, et al.: Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study. Int J Cancer 66 (2): 145-50, 1996.  [PUBMED Abstract]
    
    
27. Israel K, Sanders BG, Kline K: RRR-alpha-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways. Nutr Cancer 24 (2): 161-9, 1995.  [PUBMED Abstract]
    
    
28. Sigounas G, Anagnostou A, Steiner M: dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. Nutr Cancer 28 (1): 30-5, 1997.  [PUBMED Abstract]
    
    
29. Nakamura A, Shirai T, Takahashi S, et al.: Lack of modification by naturally occurring antioxidants of 3,2'-dimethyl-4-aminobiphenyl-initiated rat prostate carcinogenesis. Cancer Lett 58 (3): 241-6, 1991.  [PUBMED Abstract]
    
    
30. Hsing AW, Comstock GW, Abbey H, et al.: Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst 82 (11): 941-6, 1990.  [PUBMED Abstract]
    
    
31. 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 330 (15): 1029-35, 1994.  [PUBMED Abstract]
    
    
32. Peto R, Doll R, Buckley JD, et al.: Can dietary beta-carotene materially reduce human cancer rates? Nature 290 (5803): 201-8, 1981.  [PUBMED Abstract]
    
    
33. Committee on Diet, Nutrition, and Cancer, Assembly of Life Sciences, National Research Council.: Diet, Nutrition, and Cancer. Washington, DC : National Academy Press, 1982. 
    
    
34. Chan JM, Stampfer MJ, Ma J, et al.: Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev 8 (10): 893-9, 1999.  [PUBMED Abstract]
    
    
35. Li JY, Taylor PR, Li B, et al.: Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst 85 (18): 1492-8, 1993.  [PUBMED Abstract]
    
    
36. Blot WJ, Li JY, Taylor PR, et al.: Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85 (18): 1483-92, 1993.  [PUBMED Abstract]
    
    
37. Scott ML: The selenium dilemma. J Nutr 103 (6): 803-10, 1973.  [PUBMED Abstract]
    
    
38. Muth OH, Weswig PH, Whanger PD, et al.: Effect of feeding selenium-deficient ration to the subhuman primate (Saimiri sciureus). Am J Vet Res 32 (10): 1603-5, 1971.  [PUBMED Abstract]
    
    
39. Young VR: Selenium: a case for its essentiality in man. N Engl J Med 304 (20): 1228-30, 1981.  [PUBMED Abstract]
    
    
40. Milner JA: Effect of selenium on virally induced and transplantable tumor models. Fed Proc 44 (9): 2568-72, 1985.  [PUBMED Abstract]
    
    
41. Thompson HJ, Meeker LD, Becci PJ: Effect of combined selenium and retinyl acetate treatment on mammary carcinogenesis. Cancer Res 41 (4): 1413-6, 1981.  [PUBMED Abstract]
    
    
42. Thompson HJ, Wilson A, Lu J, et al.: Comparison of the effects of an organic and an inorganic form of selenium on a mammary carcinoma cell line. Carcinogenesis 15 (2): 183-6, 1994.  [PUBMED Abstract]
    
    
43. Ip C, Medina D: Current concepts of selenium and mammary tumorigenesis. In: Medina D, Kidwell W, Heppner G, et al., eds.: Cellular and Molecular Biology of Breast Cancer. New York, NY: Plenum Press, 1987, pp 479-494. 
    
    
44. Nayini JR, Sugie S, el-Bayoumy K, et al.: Effect of dietary benzylselenocyanate on azoxymethane-induced colon carcinogenesis in male F344 rats. Nutr Cancer 15 (2): 129-39, 1991.  [PUBMED Abstract]
    
    
45. el-Bayoumy K, Chae YH, Upadhyaya P, et al.: Inhibition of 7,12-dimethylbenz(a)anthracene-induced tumors and DNA adduct formation in the mammary glands of female Sprague-Dawley rats by the synthetic organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate. Cancer Res 52 (9): 2402-7, 1992.  [PUBMED Abstract]
    
    
46. el-Bayoumy K, Upadhyaya P, Desai DH, et al.: Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone tumorigenicity in mouse lung by the synthetic organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate. Carcinogenesis 14 (6): 1111-3, 1993.  [PUBMED Abstract]
    
    
47. Ip C, el-Bayoumy K, Upadhyaya P, et al.: Comparative effect of inorganic and organic selenocyanate derivatives in mammary cancer chemoprevention. Carcinogenesis 15 (2): 187-92, 1994.  [PUBMED Abstract]
    
    
48. Reddy BS, Rivenson A, Kulkarni N, et al.: Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate. Cancer Res 52 (20): 5635-40, 1992.  [PUBMED Abstract]
    
    
49. Thompson HJ, Becci PJ: Selenium inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis in the rat. J Natl Cancer Inst 65 (6): 1299-301, 1980.  [PUBMED Abstract]
    
    
50. Harr JR, Exon JH, Whanger PD, et al.: Effect of dietary selenium on N-2 fluorenyl-acetamide (FAA)-induced cancer in vitamin E supplemented, selenium depleted rats. Clin Toxicol 5 (2): 187-94, 1972.  [PUBMED Abstract]
    
    
51. Clayton CC, Baumann CA: Diet and azo dye tumors: effect of diet during a period when the dye is not fed. Cancer Res 9(10): 575-582, 1949. 
    
    
52. Shamberger RJ, Rudolph G: Protection against cocarcinogenesis by antioxidants. Experientia 22 (2): 116, 1966.  [PUBMED Abstract]
    
    
53. Reddy BS, Rivenson A, El-Bayoumy K, et al.: Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets. J Natl Cancer Inst 89 (7): 506-12, 1997.  [PUBMED Abstract]
    
    
54. Shamberger RJ: Increase of peroxidation in carcinogenesis. J Natl Cancer Inst 48 (5): 1491-7, 1972.  [PUBMED Abstract]
    
    
55. Shamberger RJ: Relationship of selenium to cancer. I. Inhibitory effect of selenium on carcinogenesis. J Natl Cancer Inst 44 (4): 931-6, 1970.  [PUBMED Abstract]
    
    
56. Jacobs MM, Jansson B, Griffin AC: Inhibitory effects of selenium on 1,2-dimethylhydrazine and methylazoxymethanol acetate induction of colon tumors. Cancer Lett 2 (3): 133-7, 1977.  [PUBMED Abstract]
    
    
57. Daoud AH, Griffin AC: Effect of retinoic acid, butylated hydroxytoluene, selenium and sorbic acid on azo-dye hepatocarcinogenesis. Cancer Lett 9 (4): 299-304, 1980.  [PUBMED Abstract]
    
    
58. Ip C, Sinha DK: Enhancement of mammary tumorigenesis by dietary selenium deficiency in rats with a high polyunsaturated fat intake. Cancer Res 41 (1): 31-4, 1981.  [PUBMED Abstract]
    
    
59. Jacobs MM: Effects of selenium on chemical carcinogens. Prev Med 9 (3): 362-7, 1980.  [PUBMED Abstract]
    
    
60. Schrauzer GN, Ishmael D: Effects of selenium and of arsenic on the genesis of spontaneous mammary tumors in inbred C3H mice. Ann Clin Lab Sci 4 (6): 441-7, 1974 Nov-Dec.  [PUBMED Abstract]
    
    
61. Shamberger RJ, Tytko SA, Willis CE: Antioxidants and cancer. Part VI. Selenium and age-adjusted human cancer mortality. Arch Environ Health 31 (5): 231-5, 1976 Sep-Oct.  [PUBMED Abstract]
    
    
62. Schrauzer GN, White DA, Schneider CJ: Cancer mortality correlation studies--III: statistical associations with dietary selenium intakes. Bioinorg Chem 7 (1): 23-31, 1977.  [PUBMED Abstract]
    
    
63. Clark LC, Cantor KP, Allaway WH: Selenium in forage crops and cancer mortality in U.S. counties. Arch Environ Health 46 (1): 37-42, 1991 Jan-Feb.  [PUBMED Abstract]
    
    
64. Salonen JT, Salonen R, Lappeteläinen R, et al.: Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data. Br Med J (Clin Res Ed) 290 (6466): 417-20, 1985.  [PUBMED Abstract]
    
    
65. Salonen JT, Alfthan G, Huttunen JK, et al.: Association between serum selenium and the risk of cancer. Am J Epidemiol 120 (3): 342-9, 1984.  [PUBMED Abstract]
    
    
66. Willett WC, Polk BF, Morris JS, et al.: Prediagnostic serum selenium and risk of cancer. Lancet 2 (8342): 130-4, 1983.  [PUBMED Abstract]
    
    
67. Kok FJ, de Bruijn AM, Hofman A, et al.: Is serum selenium a risk factor for cancer in men only? Am J Epidemiol 125 (1): 12-6, 1987.  [PUBMED Abstract]
    
    
68. Virtamo J, Valkeila E, Alfthan G, et al.: Serum selenium and risk of cancer. A prospective follow-up of nine years. Cancer 60 (2): 145-8, 1987.  [PUBMED Abstract]
    
    
69. van den Brandt PA, Goldbohm RA, van 't Veer P, et al.: A prospective cohort study on toenail selenium levels and risk of gastrointestinal cancer. J Natl Cancer Inst 85 (3): 224-9, 1993.  [PUBMED Abstract]
    
    
70. Peleg I, Morris S, Hames CG: Is serum selenium a risk factor for cancer? Med Oncol Tumor Pharmacother 2 (3): 157-63, 1985.  [PUBMED Abstract]
    
    
71. Knekt P, Aromaa A, Maatela J, et al.: Serum selenium and subsequent risk of cancer among Finnish men and women. J Natl Cancer Inst 82 (10): 864-8, 1990.  [PUBMED Abstract]
    
    
72. Glattre E, Thomassen Y, Thoresen SO, et al.: Prediagnostic serum selenium in a case-control study of thyroid cancer. Int J Epidemiol 18 (1): 45-9, 1989.  [PUBMED Abstract]
    
    
73. Broghamer WL, McConnell KP, Blotcky AL: Relationship between serum selenium levels and patients with carcinoma. Cancer 37 (3): 1384-8, 1976.  [PUBMED Abstract]
    
    
74. Shamberger RJ, Rukovena E, Longfield AK, et al.: Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. J Natl Cancer Inst 50 (4): 863-70, 1973.  [PUBMED Abstract]
    
    
75. McConnell KP, Broghamer WL Jr, Blotcky AJ, et al.: Selenium levels in human blood and tissues in health and in disease. J Nutr 105 (8): 1026-31, 1975.  [PUBMED Abstract]
    
    
76. Calautti P, Moschini G, Stievano BM, et al.: Serum selenium levels in malignant lymphoproliferative diseases. Scand J Haematol 24 (1): 63-6, 1980.  [PUBMED Abstract]
    
    
77. McConnell KP, Jager RM, Bland KI, et al.: The relationship of dietary selenium and breast cancer. J Surg Oncol 15 (1): 67-70, 1980.  [PUBMED Abstract]
    
    
78. Clark LC, Graham GF, Crounse RG, et al.: Plasma selenium and skin neoplasms: a case-control study. Nutr Cancer 6 (1): 13-21, 1984.  [PUBMED Abstract]
    
    
79. Fex G, Pettersson B, Akesson B: Low plasma selenium as a risk factor for cancer death in middle-aged men. Nutr Cancer 10 (4): 221-9, 1987.  [PUBMED Abstract]
    
    
80. Robinson MF, Godfrey PJ, Thomson CD, et al.: Blood selenium and glutathione peroxidase activity in normal subjects and in surgical patients with and without cancer in New Zealand. Am J Clin Nutr 32 (7): 1477-85, 1979.  [PUBMED Abstract]
    
    
81. Broghamer WL Jr, McConnell KP, Grimaldi M, et al.: Serum selenium and reticuloendothelial tumors. Cancer 41 (4): 1462-6, 1978.  [PUBMED Abstract]
    
    
82. Menkes MS, Comstock GW, Vuilleumier JP, et al.: Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. N Engl J Med 315 (20): 1250-4, 1986.  [PUBMED Abstract]
    
    
83. Garland M, Morris JS, Stampfer MJ, et al.: Prospective study of toenail selenium levels and cancer among women. J Natl Cancer Inst 87 (7): 497-505, 1995.  [PUBMED Abstract]
    
    
84. Schober SE, Comstock GW, Helsing KJ, et al.: Serologic precursors of cancer. I. Prediagnostic serum nutrients and colon cancer risk. Am J Epidemiol 126 (6): 1033-41, 1987.  [PUBMED Abstract]
    
    
85. Nomura A, Heilbrun LK, Morris JS, et al.: Serum selenium and the risk of cancer, by specific sites: case-control analysis of prospective data. J Natl Cancer Inst 79 (1): 103-8, 1987.  [PUBMED Abstract]
    
    
86. Knekt P, Aromaa A, Maatela J, et al.: Serum vitamin E, serum selenium and the risk of gastrointestinal cancer. Int J Cancer 42 (6): 846-50, 1988.  [PUBMED Abstract]
    
    
87. Ringstad J, Jacobsen BK, Tretli S, et al.: Serum selenium concentration associated with risk of cancer. J Clin Pathol 41 (4): 454-7, 1988.  [PUBMED Abstract]
    
    
88. Coates RJ, Weiss NS, Daling JR, et al.: Serum levels of selenium and retinol and the subsequent risk of cancer. Am J Epidemiol 128 (3): 515-23, 1988.  [PUBMED Abstract]
    
    
89. Greeder GA, Milner JA: Factors influencing the inhibitory effect of selenium on mice inoculated with Ehrlich ascites tumor cells. Science 209 (4458): 825-7, 1980.  [PUBMED Abstract]
    
    
90. Norppa H, Westermarck T, Laasonen M, et al.: Chromosomal effects of sodium selenite in vivo. I. Aberrations and sister chromatid exchanges in human lymphocytes. Hereditas 93 (1): 93-6, 1980.  [PUBMED Abstract]
    
    
91. Shamberger RJ, Beaman KD, Corlett CL, et al.: Effect of selenium and other antioxidants on the mutagenicity of malonaldehyde. [Abstract] Fed Proc 37 (3): A-265, 261, 1978. 
    
    
92. Jacobs MM, Matney TS, Griffin AC: Inhibitory effects of selenium of the mutagenicity of 2-acetylaminofluorene (AAF) and AAF derivatives. Cancer Lett 2 (6): 319-22, 1977.  [PUBMED Abstract]
    
    
93. Shamberger RJ, Baughman FF, Kalchert SL, et al.: Carcinogen-induced chromosomal breakage decreased by antioxidants. Proc Natl Acad Sci U S A 70 (5): 1461-3, 1973.  [PUBMED Abstract]
    
    
94. Griffin AC: Role of selenium in the chemoprevention of cancer. Adv Cancer Res 29: 419-42, 1979.  [PUBMED Abstract]
    
    
95. Daoud AH, Griffin AC: Effects of selenium and retinoic acid on the metabolism of N-acetylaminofluorene and N-hydroxyacetylamino-fluorene. Cancer Lett 5 (4): 231-7, 1978.  [PUBMED Abstract]
    
    
96. Marshall MV, Rasco MA, Griffin AC: Effects of selenium on benzo(a)pyrene metabolism. [Abstract] Fed Proc 37: A-628, 1383, 1978. 
    
    
97. Rasco MA, Jacobs MM, Griffin AC: Effects of selenium on aryl hydrocarbon hydroxylase activity in cultured human lymphocytes. Cancer Lett 3(5/6): 295-301, 1977. 
    
    
98. Marshall MV, Arnott MS, Jacobs MM, et al.: Selenium effects on the carcinogenicity and metabolism of 2-acetylaminofluorene. Cancer Lett 7 (6): 331-8, 1979.  [PUBMED Abstract]
    
    
99. Combs GF Jr, Scott ML: Nutritional interrelationships of vitamin E and selenium. BioScience 27(7): 467-473, 1977. 
    
    
100. Rotruck JT, Pope AL, Ganther HE, et al.: Selenium: biochemical role as a component of glutathione peroxidase. Science 179 (73): 588-90, 1973.  [PUBMED Abstract]
     
     
101. Chow CK: Nutritional influence on cellular antioxidant defense systems. Am J Clin Nutr 32 (5): 1066-81, 1979.  [PUBMED Abstract]
     
     
102. Burk RF, Lawrence RA, Lane JM: Liver necrosis and lipid peroxidation in the rat as the result of paraquat and diquat administration. Effect of selenium deficiency. J Clin Invest 65 (5): 1024-31, 1980.  [PUBMED Abstract]
     
     
103. 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. JAMA 276 (24): 1957-63, 1996.  [PUBMED Abstract]
     
     
104. Fan AM, Kizer KW: Selenium. Nutritional, toxicologic, and clinical aspects. West J Med 153 (2): 160-7, 1990.  [PUBMED Abstract]
     
     
105. Duffield-Lillico AJ, Dalkin BL, Reid ME, et al.: Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int 91 (7): 608-12, 2003.  [PUBMED Abstract]
     
     
106. Klein EA, Thompson IM, Lippman SM, et al.: SELECT: the selenium and vitamin E cancer prevention trial. Urol Oncol 21 (1): 59-65, 2003 Jan-Feb.  [PUBMED Abstract]
     
     
107. Neill MG, Fleshner NE: An update on chemoprevention strategies in prostate cancer for 2006. Curr Opin Urol 16 (3): 132-7, 2006.  [PUBMED Abstract]
     
     
108. Gerster H: The potential role of lycopene for human health. J Am Coll Nutr 16 (2): 109-26, 1997.  [PUBMED Abstract]
     
     
109. Mills PK, Beeson WL, Phillips RL, et al.: Cohort study of diet, lifestyle, and prostate cancer in Adventist men. Cancer 64 (3): 598-604, 1989.  [PUBMED Abstract]
     
     
110. Schuman LM, Mandel JS, Radke A, et al.: Some selected features of the epidemiology of prostatic cancer: Minneapolis-St. Paul, Minnesota case-control study, 1976-1979. [Abstract] Trends in Cancer Incidence: Causes and Practical Implications (Proceedings of a Symposium Held in Oslo, Norway, Aug. 6-7, 1980) pp 345-354. 
     
     
111. Le Marchand L, Hankin JH, Kolonel LN, et al.: Vegetable and fruit consumption in relation to prostate cancer risk in Hawaii: a reevaluation of the effect of dietary beta-carotene. Am J Epidemiol 133 (3): 215-9, 1991.  [PUBMED Abstract]
     
     
112. Giovannucci E, Ascherio A, Rimm EB, et al.: Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87 (23): 1767-76, 1995.  [PUBMED Abstract]
     
     
113. Jain MG, Hislop GT, Howe GR, et al.: Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada. Nutr Cancer 34 (2): 173-84, 1999.  [PUBMED Abstract]
     
     
114. Key TJ, Silcocks PB, Davey GK, et al.: A case-control study of diet and prostate cancer. Br J Cancer 76 (5): 678-87, 1997.  [PUBMED Abstract]
     
     
115. Kristal AR, Cohen JH: Invited commentary: tomatoes, lycopene, and prostate cancer. How strong is the evidence? Am J Epidemiol 151 (2): 124-7; discussion 128-30, 2000.  [PUBMED Abstract]
     
     

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