Jerzy Karkoszka

Randomized, placebo-controlled pilot trial of the effects of alpha-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.

Polycyclic Aromatic Hydrocarbons (PAH) Induce Oxidative Stress and Oxidative DNA Modification - Characteristics of Tumor Promotion

Abstract Formation of PAH-DNA base adducts is an accepted tumor-initiating event. However, it is not yet known what constitutes tumor promotional processes engendered by complete carcinogens. It appears that induction of oxidative stress and oxidative DNA damage optimally correlates with the biological effects of tumor promoters. We showed that PAH-treated rat liver microsomes produce superoxide (O2·-) and hydrogen peroxide (H2O2) that cause oxidation of bases in DNA. Recently we found that 7,12-dimethylbenz[a]anthracene (DMBA) induces in vivo some of the same responses as those mediated by phorbol ester tumor promoters. These include inflammatory processes, H2O2 production and oxidation of bases in the epidermal DNA of topically-treated SENCAR mice. Those responses occurred in long (5 wk)- and short (4 day)-term DMBA treatments. Based on these findings, we propose that PAH-induced inflammation, generation of oxidants and oxidation of bases in DNA represent tumor promotional processes of complete carcinog...