Randomized, placebo-controlled pilot trial of the effects of &agr;-tocopherol supplementation on levels of autoantibodies against 5-hydroxymethyl-2-deoxyuridine in melanoma patients

We conducted a randomized, placebo-controlled pilot trial to assess whether supplementation of 1000 mg/day &agr;-tocopherol for 3 months offered protection against DNA base damage in melanoma outpatients (n=46). Plasma autoantibodies (aAbs) against 5-hydroxymethyl-2-deoxyuridine (HMdU) were measured as an immune marker of DNA base damage. After 3 months of supplementation (final level), plasma levels of &agr;-tocopherol increased significantly (P<0.0005) in the &agr;-tocopherol compared with the placebo treatment group. Supplementation with &agr;-tocopherol also resulted in a significant (P=0.04) decrease in plasma &ggr;-tocopherol levels among males. Overall, we did not find any significant differences in the plasma anti-HMdU aAb levels between the two treatment groups. However, when the patients were stratified by the clinical characteristics of the melanoma, we found that &agr;-tocopherol supplementation resulted in a borderline significant (P=0.06) 48% decrease in plasma anti-HMdU aAb levels in patients with less aggressive melanomas (Breslow thickness ≤1 mm) only. Within-group analysis showed that women had significantly (P<0.05) higher baseline levels of anti-HMdU aAbs compared with men in each treatment group. However, the final levels of anti-HMdU aAbs were significantly (P<0.05) higher in women in the &agr;-tocopherol supplemented group only. Although reliable conclusions cannot be drawn from this pilot study, which is limited by the small sample size, the results suggest that short-term &agr;-tocopherol supplementation may offer some protection against less aggressive melanomas. Further studies using much larger sample sizes are required to confirm this finding.

[1]  M. Berwick,et al.  Quantifying the Change of Melanoma Incidence by Breslow Thickness , 2002, Biometrics.

[2]  B. Ames,et al.  Are vitamin and mineral deficiencies a major cancer risk? , 2002, Nature Reviews Cancer.

[3]  J. Luo,et al.  Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers. , 2002, Mutation research.

[4]  D. Coit,et al.  Randomized, placebo-controlled trial of dietary supplementation of α-tocopherol on mutagen sensitivity levels in melanoma patients: a pilot trial , 2002, Melanoma research.

[5]  B. Ames,et al.  gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. , 2001, The American journal of clinical nutrition.

[6]  J. Yager,et al.  The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. , 2001, Cancer research.

[7]  L. Wilkens,et al.  Association of tocopherols with circulating autoantibody levels against an oxidized DNA nucleoside in humans. , 2001, Free radical biology & medicine.

[8]  E. Cavalieri,et al.  Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol: implications for estrogen-induced initiation of renal tumors. , 2001, Chemical research in toxicology.

[9]  F. Perera,et al.  Gender differences in autoantibodies to oxidative DNA base damage in cigarette smokers. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[10]  B. Ames,et al.  DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. , 2001, Mutation research.

[11]  J. Grichnik,et al.  Identification of higher risk thin melanomas should be based on Breslow depth not Clark level IV , 2001, Cancer.

[12]  Z. Tabarowski,et al.  Immunological findings in cigarette smokers. , 2001, Toxicology letters.

[13]  J. Liehr,et al.  Estrogens as endogenous genotoxic agents--DNA adducts and mutations. , 2000, Journal of the National Cancer Institute. Monographs.

[14]  S. Thorgeirsson,et al.  Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  F. Speizer,et al.  Oral contraceptive use and risk of melanoma in premenopausal women , 1999, British Journal of Cancer.

[16]  B. Gilchrest,et al.  DNA photodamage stimulates melanogenesis and other photoprotective responses. , 1999, The journal of investigative dermatology. Symposium proceedings.

[17]  R. D'Agostino,et al.  Alpha-tocopherol dietary supplement decreases titers of antibody against 5-hydroxymethyl-2'-deoxyuridine (HMdU). , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[18]  A. Halpern,et al.  Genetic predisposition to skin cancer. , 1999, Current opinion in oncology.

[19]  C. Takahashi,et al.  Effects of high doses of vitamins C and E against doxorubicin-induced chromosomal damage in Wistar rat bone marrow cells. , 1998, Mutation research.

[20]  L. Le Marchand,et al.  Effects of beta-carotene and alpha-tocopherol on bleomycin-induced chromosomal damage. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[21]  B. Ames,et al.  Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Fenech,et al.  Vitamin-E supplements and their effect on vitamin-E status in blood and genetic damage rate in peripheral blood lymphocytes. , 1997, Carcinogenesis.

[23]  A. Collins,et al.  Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes. , 1996, Cancer research.

[24]  J. S. Morris,et al.  Serological precursors of cancer: malignant melanoma, basal and squamous cell skin cancer, and prediagnostic levels of retinol, beta- carotene, lycopene, alpha-tocopherol, and selenium. , 1995, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[25]  E. White,et al.  Case-control study of malignant melanoma in Washington State. II. Diet, alcohol, and obesity. , 1994, American journal of epidemiology.

[26]  E. Taioli,et al.  Recognition of oxidized DNA bases by sera of patients with inflammatory diseases. , 1993, Free radical biology & medicine.

[27]  V. Siskind,et al.  Diet and melanoma. An exploratory case-control study. , 1993, Annals of epidemiology.

[28]  M. Stiller,et al.  Enhanced antibody titers to an oxidized DNA base in inflammatory and neoplastic diseases , 1992, Experimental dermatology.

[29]  J. Potter,et al.  Vegetables, fruit, and cancer. II. Mechanisms , 1991, Cancer Causes & Control.

[30]  T. Louis,et al.  Diet, plasma levels of beta-carotene and alpha-tocopherol, and risk of malignant melanoma. , 1990, American journal of epidemiology.

[31]  E. Dratz,et al.  Comparison of plasma alpha and gamma tocopherol levels following chronic oral administration of either all-rac-alpha-tocopheryl acetate or RRR-alpha-tocopheryl acetate in normal adult male subjects. , 1986, The American journal of clinical nutrition.

[32]  P. McLaughlin,et al.  Vitamin E content of foods. , 1979, Journal of the American Dietetic Association.

[33]  H. Kayden,et al.  A high-performance liquid chromatographic method for the determination of tocopherol in plasma and cellular elements of the blood. , 1979, Journal of lipid research.

[34]  S. Pinnell.  Cutaneous photodamage, oxidative stress, and topical antioxidant protection. , 2003, Journal of the American Academy of Dermatology.

[35]  R. Breslow,et al.  Vitamin/mineral supplementation among cancer survivors: 1987 and 1992 National Health Interview Surveys. , 2001, Nutrition and cancer.

[36]  B. Ames,et al.  g-Tocopherol and its major metabolite , in contrast to a-tocopherol , inhibit cyclooxygenase activity in macrophages and epithelial cells , 2000 .

[37]  M. Livingstone,et al.  Dietary antioxidant supplementation and DNA damage in smokers and nonsmokers. , 1999, Nutrition and cancer.

[38]  T. Mack,et al.  The pathogenesis of melanoma induced by ultraviolet radiation. , 1999, The New England journal of medicine.

[39]  N. Dubin,et al.  Serum autoantibodies recognizing 5-hydroxymethyl-2'-deoxyuridine, an oxidized DNA base, as biomarkers of cancer risk in women. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[40]  Harvard report on cancer prevention. Causes of human cancer. Genetic susceptibility. , 1996, Cancer causes & control : CCC.

[41]  K. Helzlsouer,et al.  Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland. , 1991, The American journal of clinical nutrition.

[42]  R. Madère,et al.  Alpha- and gamma tocopherol concentrations in human serum. , 1986, Journal of the American College of Nutrition.

[43]  J. Weiter,et al.  Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. , 1985, The Journal of nutrition.

[44]  R. Doll,et al.  The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. , 1981, Journal of the National Cancer Institute.