Division of Cancer Epidemiology and Genetics (SJW, MEW, DA) and Center for Cancer Research (PRT), National Cancer Institute, NIH, DHHS, Bethesda, MD; Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland (PP, JV); Fred Hutchinson Cancer Research Center, Seattle, WA (IK); Information Management Services, Inc., Silver Spring, MD (CT)
Correspondence to: Demetrius Albanes, MD, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, EPS-3044, 9000 Rockville Pike, Bethesda, MD 20892 (e-mail: daa{at}nih.gov).
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ABSTRACT |
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-Tocopherol supplementation reduced prostate cancer incidence by 32% (95% confidence interval [CI] = 47% to 12%) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (4). Observational data regarding serum
-tocopherol and prostate cancer risk have been mixed, however (515), and few studies measured
-tocopherol (711). We therefore conducted a nested casecontrol study within the ATBC Study cohort to compare the prostate cancer risk associations of serum
-tocopherol and
-tocopherol.
The ATBC Study included 29 133 male smokers, aged 5069 years, recruited from southwestern Finland from 1985 to 1988. Subjects were provided -tocopherol and/or
-carotene supplements or placebo for 58 years. The study was approved by the institutional review boards of the National Cancer Institute and the National Public Health Institute of Finland, and written informed consent was obtained from all participants (16).
Case patients (n = 100) were randomly selected from among 246 incident prostate cancer patients ascertained through the Finnish Cancer Registry, based on the abstracted medical records, and diagnosed through April 30, 1993. The time from baseline to prostate cancer diagnosis ranged from 2.2 to 7.9 years (median, 6.1 years). Control subjects (n = 200) were alive and free of prostate cancer at the time of case patient diagnosis and were individually matched to case patients by age (within 5 years), intervention group, and date of baseline serum collection (within 15 days).
At baseline, participants completed risk factor and dietary questionnaires (17) and provided fasting serum samples (stored at 70 °C). Serum -tocopherol and
-tocopherol concentrations were determined by reverse-phase high-performance liquid chromatography, as previously described (18). Case patients and control subjects were assayed consecutively within batches along with blinded quality-control samples (n = 32). Coefficients of variation were 2.6% (within-batch) and 3.3% (between-batches) for
-tocopherol and 6.2% and 4.7%, respectively, for
-tocopherol. Serum
-carotene and cholesterol were previously measured (16,19). Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression models, adjusted for serum cholesterol. Age at randomization, body mass index, height, smoking, benign prostatic hyperplasia, physical activity, urban residence, education, and marital status were not confounders in our sample (i.e., each factor produced <10% change in tocopherol beta-coefficients). Effect modification was assessed through a cross-product term and by stratification. All P values were two-sided, and groups were considered statistically significantly different if P<.05.
Case patients had lower intake of total vitamin E but were otherwise comparable to control subjects (Table 1). In contrast to patterns in U.S. populations, -tocopherol intake exceeded
-tocopherol intake in these Finnish men. Serum
-tocopherol and
-tocopherol were highly correlated (all P< .01) with each other (Spearman r = 0.51), with intakes of total vitamin E (r = 0.22 and 0.24, respectively),
-tocopherol (r = 0.20 and 0.22),
-tocopherol (r = 0.20 and 0.33), and serum cholesterol (r = 0.61 and 0.22).
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Previous data suggest that -tocopherol supplementation decreases plasma and tissue
-tocopherol concentrations (2,20). Although for this study we assayed presupplementation serum and cannot address this issue directly, our findings indicate an inverse association for baseline serum
-tocopherol and prostate cancer risk, which was stronger among the men who were supplemented with 50 mg of
-tocopherol daily during the trial. Our previous cohort analysis showed a pattern for dietary
-tocopherol similar to that observed here for serum
-tocopherol (5). The data in the present study suggest that
-tocopherol supplementation did not negatively impact the
-tocopherol/prostate cancer association and may have strengthened it. Interestingly, the tocopherol associations were also somewhat stronger in the
-carotenesupplemented group than in those who were not given
-carotene supplements. How supplementation with either
-tocopherol or
-carotene might modify the relationship between serum tocopherol concentrations and prostate cancer risk is a matter of speculation but may involve enhanced absorption, preferential carriage, membrane transport or function, or biochemical function of the tocopherols in those who received either supplement, or it could be due to chance. Of potential relevance is our observation that men in the lowest tertile of baseline serum
-tocopherol who were given the
-tocopherol supplement did not, on average, achieve serum
-tocopherol levels as high as the baseline level of men in the highest tertile. This suggests that, even with
-tocopherol supplementation, men whose usual levels were low may not have attained a threshold serum concentration.
The antioxidant activity of vitamin E may be particularly important to the observed associations because oxidative stress has been implicated in prostate carcinogenesis (21). -Tocopherol has other important non-antioxidant functions as well, including enhancement of the immune response, modulation of gene expression, and inhibition of protein kinase C activity, cell proliferation, and cell adhesion (3,22). Recently,
-tocopheryl succinate was shown experimentally to inhibit prostate cancer cell growth through suppressed expression of the androgen receptor, prostate-specific antigen, and cell cycle regulatory proteins (23,24). We previously showed decreased androgen concentrations in response to
-tocopherol supplementation (25).
-Tocopherol has some functions that differ from those of
-tocopherol, including, for example, protection against reactive nitrogen species (1,26) and selective inhibition of cyclooxygenase activity and prostaglandin E2 synthesis (2,3).
In conclusion, higher prediagnostic circulating concentrations of the major vitamin E fraction, -tocopherol, were associated with a substantially lower risk of prostate cancer; the association with
-tocopherol was similar. The serum vitamin E concentrations measured in this study represent status prior to supplementation with
-tocopherol. In addition, the findings in this study were accentuated among men who received
-tocopherol supplementation, which may allay concerns regarding whether supplementation with
-tocopherol may negatively impact
-tocopherol status in other prevention trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) (27).
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NOTES |
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REFERENCES |
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(1) Traber MG, Arai H. Molecular mechanisms of vitamin E transport. Annu Rev Nutr 1999;19:34355.[CrossRef][ISI][Medline]
(2) Jiang Q, Christen S, Shigenaga MK, Ames BN. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74:71422.
(3) Brigelius-Flohe R, Kelly FJ, Salonen JT, Neuzil J, Zingg JM, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr 2002;76:70316.
(4) Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998;90:4406.
(5) Hartman TJ, Albanes D, Pietinen P, Hartman AM, Rautalahti M, Tangrea JA, et al. The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study. Cancer Epidemiol Biomarkers Prev 1998;7:33540.[Abstract]
(6) Eichholzer M, Stahelin HB, Gey KF, Ludin E, Bernasconi F. Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study. Int J Cancer 1996;66:14550.[CrossRef][ISI][Medline]
(7) Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 1999;59:122530.
(8) Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst 2000;92:201823.
(9) Huang HY, Alberg AJ, Norkus EP, Hoffman SC, Comstock GW, Helzlsouer KJ. Prospective study of antioxidant micronutrients in the blood and the risk of developing prostate cancer. Am J Epidemiol 2003;157:33544.
(10) Goodman GE, Schaffer S, Omenn GS, Chen C, King I. The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial. Cancer Epidemiol Biomarkers Prev 2003;12:51826.
(11) Nomura AM, Stemmermann GN, Lee J, Craft NE. Serum micronutrients and prostate cancer in Japanese Americans in Hawaii. Cancer Epidemiol Biomarkers Prev 1997;6:48791.[Abstract]
(12) Hayes RB, Bogdanovicz JF, Schroeder FH, De Bruijn A, Raatgever JW, Van der Maas PJ, et al. Serum retinol and prostate cancer. Cancer 1988;62:20216.[ISI][Medline]
(13) Knekt P, Aromaa A, Maatela J, Aaran RK, Nikkari T, Hakama M, et al. Serum vitamin E and risk of cancer among Finnish men during a 10-year follow-up. Am J Epidemiol 1988;127:2841.[Abstract]
(14) Hsing AW, Comstock GW, Abbey H, Polk BF. Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst 1990;82:9416.[Abstract]
(15) Comstock GW, Helzlsouer KJ, Bush TL. Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland. Am J Clin Nutr 1991;53:260S264S.[Abstract]
(16) The ATBC Cancer Prevention Study Group. The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. Ann Epidemiol 1994;4:110.[Medline]
(17) Pietinen P, Hartman AM, Haapa E, Rasanen L, Haapakoski J, Palmgren J, et al. Reproducibility and validity of dietary assessment instruments. I. A self-administered food use questionnaire with a portion size picture booklet. Am J Epidemiol 1988;128:65566.[Abstract]
(18) Zhang C, Williams MA, Sanchez SE, King IB, Ware-Jauregui S, Larrabure G, et al. Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women. Am J Epidemiol 2001;153:57280.
(19) Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999;30:253540.
(20) Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr 1985;115:80713.[ISI][Medline]
(21) Fleshner NE, Klotz LH. Diet, androgens, oxidative stress and prostate cancer susceptibility. Cancer Metastasis Rev 1998;17:32530.[CrossRef][ISI][Medline]
(22) Ricciarelli R, Zingg JM, Azzi A. Vitamin E: protective role of a Janus molecule. FASEB J 2001;15:231425.
(23) Zhang Y, Ni J, Messing EM, Chang E, Yang CR, Yeh S. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells. Proc Natl Acad Sci U S A 2002;99:740813.
(24) Ni J, Chen M, Zhang Y, Li R, Huang J, Yeh S. Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery. Biochem Biophys Res Commun 2003;300:35763.[CrossRef][ISI][Medline]
(25) Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, et al. Effects of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate 2001;46:338.[ISI][Medline]
(26) Traber MG. Vitamin E. In: Shils ME, Olson JA, Shike M, Ross AC, editors. Modern nutrition in health and disease. 9th ed. Baltimore (MD): Lippincott Williams & Wilkins;1999. p. 34762.
(27) Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. SELECT: the next prostate cancer prevention trial. J Urol 2001;166:13115.[ISI][Medline]
Manuscript received September 21, 2004; revised December 14, 2004; accepted December 16, 2005.
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