NCI medNews

"Prevention of prostate cancer" is redistributed by University of Bonn, Medical Center

Prevention of prostate cancer

208/05029

Get this document via a secure connection

Summary Of Evidence
Significance
Risk Factors For Prostate Cancer Development
Opportunities For Prevention

CancerMail from the National Cancer Institute

###########################################################################

!!! ATTENTION !!!

The National Cancer Institute (NCI) has updated its cancer information delivery services. In the future, please use the Cancer.gov web site (Http: //cancer.gov/) to meet your cancer information needs. CancerMail users in the United States can obtain cancer information by telephone at 1-800-4-CANCER (1-800-422-6237).

The NCI will no longer support CancerMail after November 2002. If you have comments about the NCI's cancer information delivery services, contact us by e-mail at cancer.govstaff@mail.nih.gov or call 301-496-9096.

###########################################################################

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Information from PDQ -- for Health Professionals

SUMMARY OF EVIDENCE

Note: Separate PDQ summaries on Screening for Prostate Cancer and Prostate Cancer Treatment are also available.

Prostate cancer is associated with an intact hypothalamic-pituitary-gonadal axis and in the lifetime absence of androgenic stimulation does not develop [level of evidence: 3]. Whether hormonal manipulation at various ages will modulate risk is unknown but is under investigation. A diet high in fat may increase prostate cancer risk [levels of evidence: 3,4,5]. Dietary supplementation with alpha-tocopherol and selenium may reduce risk, but studies have been inconsistent [levels of evidence: 1*,3,4,5].

Levels of Evidence for preceding statement:

1: Evidence obtained from at least one well-designed and conducted randomized controlled trial (*in this case, secondary endpoints from randomized trials)

3: Evidence obtained from well-designed and conducted cohort or case-control studies

4: Ecologic and descriptive studies (e.g., international patterns studies, migration studies, time series)

5: Opinions of respected authorities based on clinical experience or reports of expert committees

SIGNIFICANCE

Incidence and Mortality

Carcinoma of the prostate is the most common tumor in men in the United States with 189,000 new cases and 30,200 deaths expected in 2002.[1] A wide range of estimates of the impact of the disease are notable. The disease is histologically-evident in as many as 34% of men in their fifth decade and in up to 70% of men 80 years of age and older.[2,3] Prostate cancer will be diagnosed in almost one fifth of U.S. men during their lifetime, yet only 3% of men will be expected to die of the disease.[4] The estimated reduction in life expectancy of men who die of prostate cancer is approximately 9 years.[5]

The extraordinarily high rate of clinically occult prostate cancer in the general population compared to the 20-fold lower likelihood of death from the disease indicates that many of these cancers have low biologic risk. Concordant with this observation are the many series of patients with prostate cancer managed by surveillance alone with relatively good survival rates at 5 and 10 years of follow-up.[6] Data demonstrate, however, that with prolonged 10-year follow-up of moderately differentiated (which constitute the majority of tumors detected at this time [7]) and poorly differentiated tumors there is a substantial risk of disease progression and death from prostate cancer.[8]

Treatment options available for prostate cancer include radical prostatectomy, external-beam radiation therapy, brachytherapy, and surveillance. A comprehensive literature review leading to development of guidelines for prostate cancer management concluded that there are no compelling data to demonstrate the clear superiority of any of these forms of treatment for an individual patient and therefore urged the presentation of all of these treatment options to any patient with newly-diagnosed, localized prostate cancer.[9] Confounding issues in the treatment of prostate cancer include side effects with treatment, inability to predict the natural history of a given cancer, patient comorbidity that may affect an individual's likelihood of surviving long enough to be at risk for disease morbidity and mortality, as well as an increasing body of evidence suggesting that careful prostate- specific antigen (PSA) monitoring following treatment may indicate a substantial fraction of treatment failures.

Because of considerable uncertainty regarding the efficacy of treatment and the difficulty with selecting patients for whom there is a known risk of disease progression, there is division of opinion in the medical community regarding screening for carcinoma of the prostate. While both digital rectal examination and PSA have demonstrated reasonable performance characteristics (sensitivity, specificity, positive predictive value) for the early detection of prostate cancer, the lack of evidence that screening and treatment affects ultimate population morbidity or mortality has led many organizations to eschew screening.

The tremendous impact of prostate cancer on the U.S. population, as well as the financial burden of the disease both for patients and society, has led to an increased interest in primary disease prevention.

References:

  1. American Cancer Society: Cancer Facts and Figures-2002. Atlanta, Ga: American Cancer Society, 2002.
  2. Sakr WA, Haas GP, Cassin BF, et al.: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. Journal of Urology 150(2 pt 1): 379-385, 1993.
  3. Holund B: Latent prostatic cancer in a consecutive autopsy series. Scandinavian Journal of Urology and Nephrology 14(1): 29-35, 1980.
  4. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998.
  5. Horm JW, Sondik EJ: Person-years of life lost due to cancer in the United States: 1970 and 1984. American Journal of Public Health 79(11): 1490-1493, 1989.
  6. Whitmore WF Jr, Warner JA, Thompson IM: Expectant management of localized prostatic cancer. Cancer 67(4): 1091-1096, 1991.
  7. Orozco R, O'Dowd G, Kunnel B, et al.: Observations on pathology trends in 62,537 prostate biopsies obtained from urology private practices in the United States. Urology 51(2): 186-195, 1998.
  8. Albertsen PC, Murphy-Setzko MA, Hanley JA, et al.: Long term survival following conservative management of localized prostate cancer: fifteen year follow-up among men age 55-75. Journal of Urology 159(5 suppl): A963, 251, 1998.
  9. Middleton RG, Thompson IM, Austenfeld MS, et al.: Prostate Cancer Clinical Guidelines Panel summary report on the management of clinically localized prostate cancer. Journal of Urology 154(6): 2144-2148, 1995.

RISK FACTORS FOR PROSTATE CANCER DEVELOPMENT

Age

It is well-established that prostate cancer incidence increases dramatically with increasing age. While a very unusual disease in men before age 50, rates increase exponentially thereafter. The registration rate by age cohort in England and Wales increased from 8 (per thousand population) in men 50 to 56 to 68 (per thousand) in men 60 to 64, 260 (per thousand) in men 70 to 74, and peaked at 406 (per thousand) in men 75 to 79.[1] The death rate (per thousand) in 1992 in the 50 to 54, 60 to 64, and 70 to 74 aged cohorts in this same population was 4, 37, and 166, respectively.[1] At all ages, incidence of blacks exceeds those of whites. In general, the age-related increase in prostate cancer rates parallels total cancer rates in the United States.[2]

Family History

Approximately 15% of men with a diagnosis of prostate cancer will be found to have a first-degree male relative (brother, father) with prostate cancer, compared to approximately 8% of the U.S. population.[3] It has been estimated that approximately 9% of all prostate cancers may result from heritable susceptibility genes.[4] Several authors have completed segregation analyses, and although a single, rare autosomal gene has been suggested to cause cancer in some of these families, the burden of evidence suggests that the inheritance is considerably more complex.[5,6] Further study has demonstrated that, controlling for all other tumor variables, treatment of the primary tumor is more likely to fail in men with a family history of prostate cancer.[7]

Hormones

The development of the prostate is dependent upon the secretion of testosterone by the fetal testis. Testosterone causes normal virilization of the wolffian duct structures and internal genitalia and is acted upon by the enzyme 5 alpha- reductase (5AR) to form dihydrotestosterone (DHT). DHT has a fourfold to 50- fold greater affinity for the androgen receptor than testosterone, and it is DHT that leads to normal prostatic development. Children born with abnormal 5AR (due to a change in a single base pair in exon 5 of the normal type II 5AR gene), are born with ambiguous genitalia (variously-described as hypospadias with a blind-ending vagina to a small phallus) but masculinize at puberty due to the surge of testosterone production at that time. Clinical, imaging, and histologic studies of kindreds born with 5AR deficiency have demonstrated a small, pancake-appearing prostate with an undetectable prostate-specific antigen (PSA) and no evidence of prostatic epithelium.[8] Long-term follow-up demonstrates that neither benign prostatic hyperplasia (BPH) nor prostate cancer develop.

Other evidence suggesting that the degree of cumulative exposure of the prostate to androgens is related to an increased risk of prostate cancer includes:

1. Neither BPH nor prostate cancer have been reported in men castrated prior to puberty.[9]
2. Androgen levels generally parallel prostate cancer risk in various populations of men. Although there are conflicting data, a number of studies have demonstrated that levels of testosterone and, especially dihydrotestosterone, are highest in black males, of intermediate levels in white males, and lowest in native Japanese.[10-12] The risks for prostate cancer in these ethnic groups directly parallel these androgen levels.
3. Androgen deprivation in almost all forms leads to involution of the prostate, a fall in PSA levels, apoptosis of prostate cancer and epithelial cells, as well as a clinical response in prostate cancer patients.[13,14]

Race

The risk of prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese. Survival is also related to ethnicity with 5-year survivals of whites with localized, regional, or metastatic prostate cancer being 94.7%, 86.6%, and 29.6%, respectively, compared to rates of 87.8%, 69.3%, and 22.7%, respectively, for blacks.[15] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to care may play a role in disease outcomes.[16]

Dietary Fat

An interesting observation is that although the incidence of latent (occult, histologically evident) prostate cancer is similar throughout the world, clinical prostate cancer varies from country to country by as much as 20- fold.[17] Previous ecologic studies have demonstrated a direct relationship between a country's prostate cancer-specific mortality rate and average total calories from fat consumed by the country's population.[18,19] Studies of immigrants from Japan have demonstrated that native Japanese have the lowest risk of clinical prostate cancer, first generation Japanese-Americans have an intermediate risk, and subsequent generations have a risk comparable to the U.S. population.[20,21] Animal models of explanted human prostate cancer have demonstrated decreased tumor growth rates in animals fed a low-fat diet.[22,23] Evidence from many case-control studies has generally found an association between dietary fat and prostate cancer risk [24-26], although studies have not uniformly reached this conclusion.[27-29] In a review of published studies of the relationship between dietary fat and prostate cancer risk, among descriptive studies, approximately half found an increased risk with increased dietary fat and half found no association.[30] Among case-control studies, again, about half of the studies found an increased risk with increasing dietary fat, animal fat, and saturated and monounsaturated fat intake while approximately half found no association. Only in studies of polyunsaturated fat intake were there 3 reported studies of a significant negative association between prostate cancer and fat intake. In general, fat of animal origin seems to be associated with the highest risk.[16,31] In a series of 384 patients with prostate cancer, the risk of cancer progression to an advanced stage was greater in men with a high fat intake.[32] The announcement in 1996 that cancer mortality rates had fallen in the United States prompted one suggestion that this may be due to decreases in dietary fat over the same time period.[33,34]

The explanation for this possible association between prostate cancer and dietary fat is unknown. Several hypotheses have been advanced including:

1. Dietary fat may increase serum androgen levels, thereby increasing prostate cancer risk. This hypothesis is supported by observations from South Africa and the United States that changes in dietary fat change urinary and serum levels of androgens.[35,36]
2. Certain types of fatty acids or their metabolites may initiate or promote prostate carcinoma development. The evidence for this hypothesis is conflicting, but one study suggests that linoleic acid (omega-6 polyunsaturated fatty acid) may stimulate prostate cancer cells while omega-3 fatty acids inhibit cell growth.[37]
3. An observation made in an animal model is that male offspring of pregnant rats fed a high-fat diet will develop prostate cancer at a higher rate than animals fed a low-fat diet.[38] This observation may explain some of the variations in prostate cancer incidence and mortality among ethnic groups as an observation has been made that first trimester androgen levels in pregnant blacks are higher than those in whites.[39]

Diet: Fruits and Vegetables

Increased dietary intake of fruits and vegetables has been associated with a reduced risk of prostate cancer in some studies. One study evaluated 1619 prostate cancer cases and 1618 controls in a multicenter, multi-ethnic population. The study found that intake of legumes, yellow-orange, and cruciferous vegetables was associated with a lower risk of prostate cancer.[40]

Cadmium Exposure

Cadmium exposure is occupationally seen associated with nickel-cadmium batteries and cadmium recovery plant smelters as well as in association with cigarette smoke.[41] The earliest studies of this agent documented what seemed to be an association, but better-designed studies have failed to note an association.[42,43]

Dioxin Exposure

Dioxin (TCDD or 2,3,7,8 tetrachlorodibenzo-p-dioxin) is a contaminant of an herbicide used in Vietnam. This agent is similar to many components of herbicides used in farming. In the review of the linkage between dioxin and prostate cancer risk by the National Academy of Sciences Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, only 2 articles were found on prostate cancer with sufficient numbers of cases and follow-up to allow analysis.[44,45] Their analysis of all available data suggest that the association between dioxin exposure and prostate cancer is not conclusive.[46]

References:

  1. Epidemiological aspects. In: Kirby RS, Christmas TJ, Brawer MK: Prostate Cancer. London, England: Mosby, 1996, pp 23-32.
  2. Cancer incidence in the United States (SEER) age-specific rates. In: Harras A, Edwards BK, Blot WJ, eds., et al.: Cancer Rates and Risks. 4th ed., Bethesda, Md: National Cancer Institute, 1996, pp 22.
  3. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. The Prostate 17(1): 337-347, 1990.
  4. Gronberg H, Isaacs SD, Smith JR, et al.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA: Journal of the American Medical Association 278(15): 1251-1255, 1997.
  5. Carter BS, Steinberg GD, Beaty TH, et al.: Familial risk factors for prostate cancer. Cancer Surveys 11: 5-13, 1991.
  6. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. American Journal of Human Genetics 62(6): 1425-1438, 1998.
  7. Kupelian PA, Klein EA, Witte JS, et al.: Familial prostate cancer: a different disease? Journal of Urology 158(6): 2197-2201, 1997.
  8. Imperato-McGinley J, Gautier T, Zirinsky K, et al.: Prostate visualization studies in males homozygous and heterozygous for 5alpha-reductase deficiency. Journal of Clinical Endocrinology and Metabolism 75(4): 1022-1026, 1992.
  9. Isaacs JT: Hormonal balance and the risk of prostatic cancer. Journal of Cellular Biochemistry 16H(suppl): 107-108, 1992.
  10. Ellis L, Nyborg H: Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 57(2): 72-75, 1992.
  11. Ross RK, Bernstein L, Lobo RA, et al.: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339(8798): 887-889, 1992.
  12. Wu AH, Whittemore AS, Kolonel LN, et al.: Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiology, Biomarkers and Prevention 4(7): 735-741, 1995.
  13. Peters CA, Walsh PC: The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. New England Journal of Medicine 317(10): 599-604, 1987.
  14. Kyprianou N, Isaacs JT: Expression of transforming growth factor-beta in the rat ventral prostate during castration-induced programmed cell death. Molecular Endocrinology 3(10):1515-1522, 1989.
  15. Ries LA, Miller BA, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1991: tables and graphs. Bethesda, Md: National Cancer Institute, 371. NIH Pub. No. 94-2789, 1994.
  16. Optenberg SA, Thompson IM, Friedrichs P, et al.: Race, treatment, and long-term survival from prostate cancer in an equal-access medical care delivery system. JAMA: Journal of the American Medical Association 274(20): 1599-1605, 1995.
  17. Wynder EL, Mabuchi K, Whitmore WF Jr: Epidemiology of cancer of the prostate. Cancer 28(2): 344-360, 1971.
  18. Armstrong B, Doll R: Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. International Journal of Cancer 15(4): 617-631, 1975.
  19. Rose DP, Connolly JM: Dietary fat, fatty acids and prostate cancer. Lipids 27(10): 798-803, 1992.
  20. Haenszel W, Kurihara M: Studies of Japanese migrants, I: mortality from cancer and other disease among Japanese in United States. Journal of the National Cancer Institute 40(1): 43-68, 1968.
  21. Shimizu H, Ross RK, Bernstein L, et al.: Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. British Journal of Cancer 63(6): 963-966, 1991.
  22. Wang Y, Corr JG, Thaler HT, et al.: Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet. Journal of the National Cancer Institute 87(19): 1456-1462, 1995.
  23. Connolly JM, Coleman M, Rose DP: Effects of dietary fatty acids on DU145 human prostate cancer cell growth in athymic nude mice. Nutrition and Cancer 29(2): 114-119, 1997.
  24. Ross RK, Shimizu H, Paganini-Hill A, et al.: Case-control studies of prostate cancer in blacks and whites in southern California. Journal of the National Cancer Institute 78(5): 869-874, 1987.
  25. Kolonel LN, Yoshizawa CN, Hankin JH: Diet and prostatic cancer: a case-control study in Hawaii. American Journal of Epidemiology 127(5): 999-1012, 1988.
  26. Whittemore AS, Kolonel LN, Wu AH, et al.: Prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and Asians in the United States and Canada. Journal of the National Cancer Institute 87(9): 652-661, 1995.
  27. Giovannucci E: Epidemiologic characteristics of prostate cancer. Cancer 75(suppl 7): 1766-1777, 1995.
  28. Mettlin C, Selenskas S, Natarajan N, et al.: Beta-carotene and animal fats and their relationship to prostate cancer risk: a case-control study. Cancer 64(3): 605-612, 1989.
  29. Severson RK, Nomura AM, Grove JS, et al.: A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Research 49(7): 1857-1860, 1989.
  30. Zhou JR, Blackburn GL: Bridging animal and human studies: what are the missing segments in dietary fat and prostate cancer? American Journal of Clinical Nutrition 66(suppl): 1572S-1580S, 1997.
  31. Rose DP, Boyar AP, Wynder EL: International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 58(11): 2363-2371, 1986.
  32. Bairati I, Meyer F, Fradet Y, et al.: Dietary fat and advanced prostate cancer. Journal of Urology 159(4): 1271-1275, 1998.
  33. Cole P, Rodu B: Declining cancer mortality in the United States. Cancer 78(10): 2045-2048, 1996.
  34. Wynder EL, Cohen LA: Correlating nutrition to recent cancer mortality statistics. Journal of the National Cancer Institute 89(4): 324, 1997.
  35. Hill P, Wynder EL, Garbaczewski L, et al.: Diet and urinary steroids in black and white North American men and black South African men. Cancer Research 39(12): 5101-5105, 1979.
  36. Hamalainen E, Adlercreutz H, Puska P, et al.: Diet and serum sex hormones in healthy men. Journal of Steroid Biochemistry 20(1): 459-464, 1984.
  37. Rose DP, Connolly JM: Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. The Prostate 18(3): 243-254, 1991.
  38. Kondo Y, Homma Y, Aso Y, et al.: Promotional effect of two-generation exposure to a high-fat diet on prostate carcinogenesis in ACI/Seg rats. Cancer Research 54(23): 6129-6132, 1994.
  39. Henderson BE, Bernstein L, Ross RK, et al.: The early in utero oestrogen and testosterone environment of blacks and whites: potential effects on male offspring. British Journal of Cancer 57(2): 216-218, 1988.
  40. Kolonel LN, Hankin JH, Whittemore AS, et al.: Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiology, Biomarkers and Prevention 9(8): 795-804, 2000.
  41. Pienta KJ: Epidemiology and etiology of prostate cancer. In: Raghavan D, Scher HI, Leibel SA, eds., et al.: Principles and Practice of Genitourinary Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 379-385.
  42. Sanchez AG, Antona JF, Urrutia M: Geochemical prospection of cadmium in a high incidence area of prostate cancer, Sierra de Gata, Salamanca, Spain. The Science of the Total Environment 116(3): 243-251, 1992.
  43. Boffetta P: Methodological aspects of the epidemiological association between cadmium and cancer in humans. In: Nordberg GF, Herber RF, Alessio L, eds.: Cadmium in the Human Environment: Toxicity and Carcinogenicity. Lyon, France: International Agency for Research on Cancer, 1992, pp 425-434.
  44. Fingerhut MA, Halperin WE, Marlow DA, et al.: Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. New England Journal of Medicine 324(4): 212-218, 1991.
  45. Bertazzi PA, Zocchetti C, Pesatori AC, et al.: Ten-year mortality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiology 129(6): 1187-1200, 1989.
  46. Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides: Veterans and Agent Orange: Update 1996. Washington DC, National Academy Press, 1996.

OPPORTUNITIES FOR PREVENTION

Hormonal Prevention

The evidence that lifetime hormonal influences may affect prostate cancer risk has led to the initiation of a large, randomized, placebo-controlled trial of finasteride (an inhibitor of 5 alpha-reductase) to determine if this agent can reduce the incidence of prostate carcinoma.[1] The results of this study will not be available until approximately 2004. In general, agents that are used for hormonal therapy of existing prostate cancers would be unsuitable for prostate cancer chemoprevention due to the cost and wide variety of side effects including sexual dysfunction, osteoporosis, and vasomotor symptoms (hot flushes).[2] It is possible, however, that newer antiandrogens may play a role as preventive agents in the future.[3]

Dietary Prevention With a Low-Fat Diet

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.

Chemoprevention

Several agents, including alpha-tocopherol, selenium, lycopene, difluoromethylornithine (DFMO),[4-8] vitamin D,[9-11] and isoflavonoids,[12,13] 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 our chemoprevention discussions below.

Chemoprevention With Vitamin E (Alpha-Tocopherol)

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.[14] The study, employing d-alpha-tocopheryl acid succinate, found that not only did it enhance the cytotoxic effect of adriamycin but also inhibited cell growth when used alone. This inhibition was dose-dependent. Finally, these properties were noted at doses which are routinely attained in plasma.[15] These same doses have been demonstrated to have no effect on normal mouse fibroblasts.[16,17] In a similar study using the Nb rat prostate adenocarcinoma model, it was found that the combination of adriamycin-vitamin E resulted in a lower average final tumor volume when compared to control animals.[18]

A nested case-control study of serum micronutrients from a cohort of 6,860 Japanese-American men analyzed 142 confirmed cases of prostate cancer, comparing them with a similar number of controls.[19] Although the difference did not reach statistical significance, the odds ratio for gamma-tocopherol was 0.7 (95% confidence interval 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 significantly increased risk for lung cancer.[20] Additionally, it was noted in male smokers that 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 3 metastatic human prostate cancer cell lines was studied: LNCaP, PC-3, and DU-145.[21] It was found that VES inhibited cell growth and 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.[22] It was observed that 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 due to vitamin E supplementation.

Not all studies of alpha-tocopherol have found the agents to be effective. Using the DMAB-initiated rate prostate cancer model in F344 rats, the effect of 6 naturally occurring antioxidants on carcinogenesis was studied.[23] 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.[24] Serum levels of tocopherol were compared between 103 men who developed prostate cancer during 13 years of follow-up to 103 control subjects 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 incidence of lung cancer in male smokers.[25] 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.[26,27] 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 2 capsules. Specifically, participants were divided into 4 similar study arms/groups: 1 receiving beta-carotene and placebo, 1 receiving alpha-tocopherol and placebo, 1 receiving both active agents, and 1 receiving 2 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,[14] 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 randomized to receive alpha-tocopherol (99 prostate cancers) than in those who were not randomized 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.[28] 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 [29,30], also tested alpha- tocopherol, along with selenium (discussed below) and various other agents, in humans. The Linxian general population trial involved approximately 30,000 subjects 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 ug/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 significantly lower gastric cancer (cardia plus noncardia) mortality rate (a major cancer in Linxian). A second, far smaller Linxian trial (in approximately 3,300 subjects) tested a combination of these 3 agents along 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 2 Linxian trials, however, because the trials differed in scale, subject 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 also 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.

Chemoprevention With Selenium

Selenium is an essential trace element in humans and in other species.[31-33] A substantial volume of data suggest that supplementation with selenium reduces the risk of a variety of cancers in chemically-induced cancers [34-52], in spontaneous animal tumors [53], and in transplanted animal tumor lines.[54] Studies of geographical areas with varying dietary selenium content have demonstrated an inverse relationship between selenium intake and cancer risk.[55,56] Similarly, in a study of environmental selenium levels (forage crop concentrations of selenium), an inverse relationship was again noted.[57] Epidemiologic studies have had mixed results with statistically significant (again, inverse) relationships encountered in some studies [58-73] while others have not encountered a statistically-higher risk in patients with low selenium levels or a low selenium intake.[74-82]

In a case-control study, serum samples collected in 1973 from 111 subjects who developed cancer during the subsequent 5 years were studied and compared with serum samples from 210 cancer-free subjects matched for age, race, sex, and smoking history.[60] Subjects 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 +/- SEM 0.002 ug/ml) than in controls (0.126 +/- 0.002 ug/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 culture, it reduces the effect of a number of described mutagens [83-87] and may alter the metabolism of other carcinogens.[88-92] A variety of other potential actions which 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.[25,93-96]

A multi-institutional study designed to prevent skin cancer randomized a group of 1,312 patients with a history of basal cell or squamous cell carcinoma of the skin to either 200 ug selenium per day (as selenized yeast) or placebo (nonselenized yeast).[97] Although the study began in 1983, additional funding subsequently allowed the ascertainment of rates of other cancers in the 2 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 2 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. It is important to note that no patient experienced toxicity due to selenosis, a side effect that has been reported in association with chronic feeding of inorganic and certain organic forms of selenium at levels above 5 ppm.[98] 

       Cancer Incidence in Study of Clark: Randomized Trial of Selenium

-------------------------------------------------------------------------------
Cancer Site            Selenium   Placebo   Hazard Ratio     p value
------------------------------------------------------------------------------
Lung                       17        31          .56           .05
Prostate                   13        35          .35           .001
Colorectal                  8        19          .39           .03
Head/neck                   6         8          .77           .64
Bladder                     8         6         1.27           .66
Esophageal                  2         6          .30           .14
Breast                      9         3         2.95           .11
Other carcinoma             5         9          .54           .27
Total carcinoma            59       104          .54          <.001

Melanoma                    8         8          .92           .87
Leukemia                    8         5         1.50           .48
Other noncarcinoma          3         3          .99           .99
Total noncarcinomas        19        16         1.16           .65
Total cancers              77       119          .61          <.001

Other clinical trials of selenium in humans include the 2 studies conducted in Linxian, China [29,30], that are discussed above in the "Chemoprevention with Vitamin E (Alpha-Tocopherol)" section.

Chemoprevention With Lycopene

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.[99] 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 subjects showing a reduced risk.[100-103] 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 compared to the group with the lowest level of consumption, which they attributed to the lycopene content of these vegetables.[104] This large analysis prompted several subsequent studies, the results of which were mixed.[105,106] 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 in general), dietary intake instruments are poorly able to quantify lycopene intake, and other potential biases.[107] Specific dietary supplementation with lycopene remains to be demonstrated to reduce prostate cancer risk.

References:

  1. Thompson IM, Coltman CA Jr, Crowley J: Chemoprevention of prostate cancer: the Prostate Cancer Prevention Trial. The Prostate 33(3): 217-221, 1997.
  2. Thompson I, Feigl P, Coltman C: Chemoprevention of prostate cancer with finasteride. In: DeVita VT, Hellman S, Rosenberg SA, eds.: Important Advances in Oncology 1995. Philadelphia, Pa: J.B. Lippincott Co., 1995, pp 57-76.
  3. Nelson PS, Gleason TP, Brawer MK: Chemoprevention for prostatic intraepithelial neoplasia. European Urology 30(2): 269-278, 1996.
  4. Heby O: Role of polyamines in the control of cell proliferation and differentiation. Differentiation 19(1): 1-20, 1981.
  5. 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 Sciences 24(6): 519-524, 1979.
  6. 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. Journal of the American Chemical Society 100(8): 2551-2553, 1978.
  7. 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. The Prostate 3(4): 383-389, 1982.
  8. Abeloff MD, Slavik M, Luk GD, et al.: Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine: an inhibitor of polyamine biosynthesis. Journal of Clinical Oncology 2(2): 124-130, 1984.
  9. Schwartz GG, Hulka BS: Is vitamin D deficiency a risk factor for prostate cancer? (hypothesis). Anticancer Research 10(5A): 1307-1311, 1990.
  10. Eisman JA, Barkla DH, Tutton PJ: Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Research 47(1): 21-25, 1987.
  11. Chida K, Hashiba H, Fukushima M, et al.: Inhibition of tumor promotion in mouse skin by 1 alpha,25-dihydroxyvitamin D3. Cancer Research 45 (11 pt 1): 5426-5430, 1985.
  12. Adlercreutz H, Markkanen H, Watanabe S: Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342(8881): 1209-1210, 1993.
  13. Peterson G, Barnes S: Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. The Prostate 22(4): 335-345, 1993.
  14. Ripoll EA, Rama BN, Webber MM: Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro. Journal of Urology 136(2): 529-531, 1986.
  15. Gilbert HS, Stump DD, Ginsberg H, et al.: The effect of chronic hypocholesterolemia in myeloproliferative disease on the distribution of plasma and erythrocyte tocopherol. American Journal of Clinical Nutrition 40(1): 95-100, 1984.
  16. Prasad KN, Edwards-Prasad J: Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Research 42(2): 550-555, 1982.
  17. Landolph JR, Bhatt RS, Telfer N, et al.: Comparison of adriamycin- and ouabain-induced cytotoxicity and inhibition of rubidium86 transport in wild-type and ouabain-resistant C3H/10T1/2 mouse fibroblasts. Cancer Research 40(12): 4581-4588, 1980.
  18. Nesbitt JA, Smith J, McDowell G, et al.: Adriamycin-vitamin E combination therapy for treatment of prostate adenocarcinoma in the Nb rat model. Journal of Surgical Oncology 38(4): 283-284, 1988.
  19. Nomura AM, Stemmermann GN, Lee J, et al.: Serum micronutrients and prostate cancer in Japanese Americans in Hawaii. Cancer Epidemiology, Biomarkers and Prevention 6(7): 487-491, 1997.
  20. Eichholzer M, Stahelin 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. International Journal of Cancer 66(2): 145-150, 1996.
  21. Israel K, Sanders BG, Kline K: RRR-alpha-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways. Nutrition and Cancer 24(2): 161-169, 1995.
  22. Sigounas G, Anagnostou A, Steiner M: dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. Nutrition and Cancer 28(1): 30-35, 1997.
  23. Nakamura A, Shirai T, Takahashi T, et al.: Lack of modification by naturally occurring antioxidants of 3,2'-dimethyl-4-aminobiphenyl-initiated rat prostate carcinogenesis. Cancer Letters 58(3): 241-246, 1991.
  24. Hsing AW, Comstock GW, Abbey H, et al.: Serologic precursors of cancer: retinol, carotenoids, and tocopherol and risk of prostate cancer. Journal of the National Cancer Institute 82(11): 941-946, 1990.
  25. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine 330(15): 1029-1035, 1994.
  26. Peto R, Doll R, Buckley JD, et al.: Can dietary beta-carotene materially reduce human cancer rates? Nature 290(5803): 201-208, 1981.
  27. Committee on Diet, Nutrition, and Cancer, Assembly of Life Sciences, National Research Council: Diet, Nutrition, and Cancer. Washington, DC : National Academy Press, 1982.
  28. 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 Epidemiology, Biomarkers and Prevention 8(10): 893-899, 1999.
  29. 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. Journal of the National Cancer Institute 85(18): 1492-1498, 1993.
  30. 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. Journal of the National Cancer Institute 85(18): 1483-1492, 1993.
  31. Scott ML: The selenium dilemma. Journal of Nutrition 103(6): 803-810, 1973.
  32. Muth OH, Weswig PH, Whanger PD, et al.: Effect of feeding selenium-deficient ration to the subhuman primate (Saimiri sciureus). American Journal of Veterinary Research 32(10): 1603-1605, 1971.
  33. Young VR: Selenium: a case for its essentiality in man. New England Journal of Medicine 304(20): 1228-1230, 1981.
  34. Milner JA: Effect of selenium on virally induced and transplantable tumor models. Federation Proceedings 44(9): 2568-2572, 1985.
  35. Thompson HJ, Meeker LD, Becci PJ: Effect of combined selenium and retinyl acetate treatment on mammary carcinogenesis. Cancer Research 41(4): 1413-1416, 1981.
  36. 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): 183-186, 1994.
  37. 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.
  38. Nayini JR, Sugie S, El-Bayoumy K, et al.: Effect of dietary benzylselenocyanate on azoxymethane-induced colon carcinogenesis in male F344 rats. Nutrition and Cancer 15(2): 129-139, 1991.
  39. 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 Research 52(9): 2402-2407, 1992.
  40. 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): 1111-1113, 1993.
  41. Ip C, El-Bayoumy K, Upadhyaya P, et al.: Comparative effect of inorganic and organic selenocyanate derivatives in mammary cancer chemoprevention. Carcinogenesis 15(2): 187-192, 1994.
  42. Reddy BS, Rivenson A, Kulkarni N, et al.: Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate. Cancer Research 52(20): 5635-5640, 1992.
  43. Thompson HJ, Becci PJ: Selenium inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis in the rat. Journal of the National Cancer Institute 65(6): 1299-1301, 1980.
  44. 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. Clinical Toxicology 5(2): 187-194, 1972.
  45. Clayton CC, Baumann CA: Diet and azo dye tumors: effect of diet during a period when the dye is not fed. Cancer Research 9(10): 575-582, 1949.
  46. Shamberger RJ, Rudolph G: Protection against cocarcinogenesis by antioxidants. Experientia 22(2): 116, 1966.
  47. Reddy BS, Rivenson A, El-Bayoumy K, et al.: Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets. Journal of the National Cancer Institute 89(7): 506-512, 1997.
  48. Shamberger RJ: Increase of peroxidation in carcinogenesis. Journal of the National Cancer Institute 48(5): 1491-1497, 1972.
  49. Shamberger RJ: Relationship of selenium to cancer, I: inhibitory effect of selenium on carcinogenesis. Journal of the National Cancer Institute 44(4): 931-936, 1970.
  50. Jacobs MM, Jansson B, Griffin AC: Inhibitory effects of selenium on 1,2-dimethylhydrazine and methylazoxymethanol acetate induction of colon tumors. Cancer Letters 2(3): 133-137, 1977.
  51. Daoud AH, Griffin AC: Effect of retinoic acid, butylated hydroxytoluene, selenium and sorbic acid on azo-dye hepatocarcinogenesis. Cancer Letters 9(4): 299-304, 1980.
  52. Ip C, Sinha DK: Enhancement of mammary tumorigenesis by dietary selenium deficiency in rats with a high polyunsaturated fat intake. Cancer Research 41(1): 31-34, 1981.
  53. Jacobs MM: Effects of selenium on chemical carcinogens. Preventive Medicine 9(3): 362-367, 1980.
  54. Schrauzer GN, Ishmael D: Effects of selenium and of arsenic on the genesis of spontaneous mammary tumors in inbred C3H mice. Annals of Clinical and Laboratory Science 4(6): 441-447, 1974.
  55. Shamberger RJ, Tytko SA, Willis CE: Antioxidants and cancer, part VI: selenium and age-adjusted human cancer mortality. Archives of Environmental Health 31(5): 231-235, 1976.
  56. Schrauzer GN, White DA, Schneider CJ: Cancer mortality correlation studies-III: statistical associations with dietary selenium intakes. Bioinorganic Chemistry 7(1): 23-34, 1977.
  57. Clark LC, Cantor KP, Allaway WH: Selenium in forage crops and cancer mortality in U.S. counties. Archives of Environmental Health 46(1): 37-42, 1991.
  58. Salonen JT, Salonen R, Lappetelainen 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. British Medical Journal (Clinical Research Edition) 290(6466): 417-420, 1985.
  59. Salonen JT, Alfthan G, Huttunen JK, et al.: Association between serum selenium and the risk of cancer. American Journal of Epidemiology 120(3): 342-349, 1984.
  60. Willett WC, Polk BF, et al, on behalf of the Hypertension Detection and Follow-up Program Cooperative Group: Prediagnostic serum selenium and risk of cancer. Lancet 2(8342): 130-134, 1983.
  61. Kok FJ, de Bruijn AM, Hofman A, et al.: Is serum selenium a risk factor for cancer in men only? American Journal of Epidemiology 125(1): 12-16, 1987.
  62. Virtamo J, Valkeila E, Alfthan G, et al.: Serum selenium and risk of cancer: a prospective follow-up of nine years. Cancer 60(2): 145-148, 1987.
  63. 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. Journal of the National Cancer Institute 85(3): 224-229, 1993.
  64. Peleg I, Morris S, Hames CG: Is serum selenium a risk factor for cancer? Medical Oncology and Tumor Pharmacotherapy 2(3): 157-163, 1985.
  65. Knekt P, Aromaa A, Maatela J, et al.: Serum selenium and subsequent risk of cancer among Finnish men and women. Journal of the National Cancer Institute 82(10): 864-868, 1990.
  66. Glattre E, Thomassen Y, Thoresen SO, et al.: Prediagnostic serum selenium in a case-control study of thyroid cancer. International Journal of Epidemiology 18(1): 45-49, 1989.
  67. Broghamer WL Jr, McConnell KP, Blotcky AL: Relationship between serum selenium levels and patients with carcinoma. Cancer 37(3): 1384-1388, 1976.
  68. Shamberger RJ, Rukovena E, Longfield AK, et al.: Antioxidants and cancer, I: selenium in the blood of normals and cancer patients. Journal of the National Cancer Institute 50(4): 863-870, 1973.
  69. McConnell KP, Broghamer WL Jr, Blotcky AJ, et al.: Selenium levels in human blood and tissues in health and in disease. Journal of Nutrition 105(8): 1026-1031, 1975.
  70. Calautti P, Moschini G, Stievano BM, et al.: Serum selenium levels in malignant lymphoproliferative diseases. Scandinavian Journal of Haematology 24(1): 63-66, 1980.
  71. McConnell KP, Jager RM, Bland KI, et al.: The relationship of dietary selenium and breast cancer. Journal of Surgical Oncology 15(1): 67-70, 1980.
  72. Clark LC, Graham GF, Crounse RG, et al.: Plasma selenium and skin neoplasms: a case-control study. Nutrition and Cancer 6(1): 13-21, 1984.
  73. Fex G, Pettersson B, Akesson B: Low plasma selenium as a risk factor for cancer death in middle-aged men. Nutrition and Cancer 10(4): 221-229, 1987.
  74. 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. American Journal of Clinical Nutrition 32(7): 1477-1485, 1979.
  75. Broghamer WL Jr, McConnell KP, Grimaldi M, et al.: Serum selenium and reticuloendothelial tumors. Cancer 41(4): 1462-1466, 1978.
  76. Menkes MS, Comstock GW, Vuilleumier JP, et al.: Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. New England Journal of Medicine 315(20): 1250-1254, 1986.
  77. Garland M, Morris JS, Stampfer MJ, et al.: Prospective study of toenail selenium levels and cancer among women. Journal of the National Cancer Institute 87(7): 497-505, 1995.
  78. Schober SE, Comstock GW, Helsing KJ, et al.: Serologic precursors of cancer, I: prediagnostic serum nutrients and colon cancer risk. American Journal of Epidemiology 126(6): 1033-1041, 1987.
  79. Nomura A, Heilbrun LK, Morris JS, et al.: Serum selenium and the risk of cancer, by specific sites: case-control analysis of prospective data. Journal of the National Cancer Institute 79(1): 103-108, 1987.
  80. Knekt P, Aromaa A, Maatela J, et al.: Serum vitamin E, serum selenium and the risk of gastrointestinal cancer. International Journal of Cancer 42(6): 846-850, 1988.
  81. Ringstad J, Jacobsen BK, Tretli S, et al.: Serum selenium concentration associated with risk of cancer. Journal of Clinical Pathology 41(4): 454-457, 1988.
  82. Coates RJ, Weiss NS, Daling JR, et al.: Serum levels of selenium and retinol and the subsequent risk of cancer. American Journal of Epidemiology 128(3): 515-523, 1988.
  83. Greeder GA, Milner JA: Factors influencing the inhibitory effect of selenium on mice inoculated with Ehrlich ascites tumor cells. Science 209(4458): 825-827, 1980.
  84. 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): 93-96, 1980.
  85. Shamberger RJ, Beaman KD, Corlett CL, et al.: Effect of selenium and other antioxidants on the mutagenicity of malonaldehyde. Federation Proceedings 37(3): A265, 261, 1978.
  86. Jacobs MM, Matney TS, Griffin AC: Inhibitory effects of selenium on the mutagenicity of 2-acetylaminofluorene (AAF) and AAF derivatives. Cancer Letters 2(6): 319-322, 1977.
  87. Shamberger RJ, Baughman FF, Kalchert SL, et al.: Carcinogen-induced chromosomal breakage decreased by antioxidants. Proceedings of the National Academy of Sciences 70(5): 1461-1463, 1973.
  88. Griffin AC: Role of selenium in the chemoprevention of cancer. Advances in Cancer Research 29: 419-442, 1979.
  89. Daoud AH, Griffin AC: Effects of selenium and retinoic acid on the metabolism of N-acetylaminofluorene and N-hydroxyacetylamino-fluorene. Cancer Letters 5(4): 231-237, 1978.
  90. Marshall MV, Rasco MA, Griffin AC: Effects of selenium on benzo(a)pyrene metabolism. Federation Proceedings 37: A628, 1383, 1978.
  91. Rasco MA, Jacobs MM, Griffin AC: Effects of selenium on aryl hydrocarbon hydroxylase activity in cultured human lymphocytes. Cancer Letters 3(5/6): 295-301, 1977.
  92. Marshall MV, Arnott MS, Jacobs MM, et al.: Selenium effects on the carcinogenicity and metabolism of 2-acetylaminofluorene. Cancer Letters 7(6): 331-338, 1979.
  93. Combs GF Jr, Scott ML: Nutritional interrelationships of vitamin E and selenium. BioScience 27(7): 467-473, 1977.
  94. Rotruck JT, Pope AL, Ganther HE, et al.: Selenium: biochemical role as a component of glutathione peroxidase. Science 179(73): 588-590, 1973.
  95. Chow CK: Nutritional influence on cellular antioxidant defense systems. American Journal of Clinical Nutrition 32(5): 1066-1081, 1979.
  96. 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. Journal of Clinical Investigation 65(5): 1024-1031, 1980.
  97. 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. JAMA: Journal of the American Medical Association 276(24): 1957-1963, 1996.
  98. Fan AM, Kizer KW: Selenium: nutritional, toxicologic, and clinical aspects. Western Journal of Medicine 153(2): 160-167, 1990.
  99. Gerster H: The potential role of lycopene for human health. Journal of the American College of Nutrition 16(2): 109-126, 1997.
  100. 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.
  101. 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. In: Magnus K, ed: Trends in Cancer Incidence: Causes and Practical Implications (Proceedings of a Symposium Held in Oslo, Norway, Aug. 6-7, 1980). Washington, DC: Hemisphere Publishing Corp, 1982, pp 345-354.
  102. 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. American Journal of Epidemiology 133(3): 215-219, 1991.
  103. Hsing AW, Comstock GW, Abbey H, et al.: Serologic precursors of cancer: retinol, carotenoids, and tocopherol and risk of prostate cancer. Journal of the National Cancer Institute 82(11): 941-946, 1990.
  104. Giovannucci E, Ascherio A, Rimm EB, et al.: Intake of carotenoids and retinol in relation to risk of prostate cancer. Journal of the National Cancer Institute 87(23): 1767-1776, 1995.
  105. Jain MG, Hislop GT, Howe GR, et al.: Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada. Nutrition and Cancer 34(2): 173-184, 1999.
  106. Key TJ, Silcocks PB, Davey GK, et al.: A case-control study of diet and prostate cancer. British Journal of Cancer 76(5): 678-687, 1997.
  107. Kristal AR, Cohen JH: Invited commentary: tomatoes, lycopene, and prostate cancer. How strong is the evidence? American Journal of Epidemiology 151(2): 124-127, 2000.
Date Last Modified: 06/2002

This information from PDQ is reviewed regularly by members of the PDQ Editorial Boards. If you have specific comments on the content of this information, direct them to: PDQ Editorial Board, CIPS/NCI, 6116 Executive Boulevard, Suite 3002B, MSC-8321, 20892-8321, fax: 301-480-8105. * * The PDQ database also contains listings of clinical trial protocols and directories of organizations and physicians who treat cancer patients, but this information is not available through CancerMail. For more information on accessing PDQ, consult the CancerMail Contents List.

MEDEVENT Congress Server Browse and Submit Oncology Conferences

Sponsors:

  <A HREF ="deutsch/CancernetDSL.ram">Play clip using the stand-alone RealPlayer!</A><A HREF ="http://www.real.com/products/player/d1.html">Click here to download the latest RealPlayer!</A>
small video clip about our work (200 Kbit/s)


Back to the Cancernet contents overview
Questions? Mail them to us!		 We subscribe to the HON-Code principles of the Health On the Net Foundation We subscribe to the HONcode principles
of the Health On the Net Foundation


Dr. G. Quade
This page was last modified on Sunday, 02-Nov-2003 15:58:33 CET
Impressum