The amount of beta-carotene in the diet has emerged as a significant inverse predictor of cancer risk in numerous epidemiologic investigations. Mechanistic rationale for the use of this agent in cancer prevention is substantial. It has a high affinity for singlet oxygen and thus, may prevent free radical formation and resultant DNA damage. In addition, beta-carotene is converted in vivo to retinoids, which have been shown to inhibit proliferation of neoplastic cells and stimulate cellular differentiation. Recent studies have also noted an immunomodulating effect of beta-carotene as evidenced by increased numbers of NK cells and activated monocytes. In addition,t he toxicity profile of this agent is extremely favorable, as would be necessary for a successful chemopreventive agent. Despite a high level of clinical interest in this compound, a comprehensive description of the pharmacokinetics and pharmacodynamics are lacking. This proposal is designed to address these issues, first, in tobacco smokers and secondly, when beta-carotene is administered in combination with Vitamin E. The first study is a blinded, parallel design trial in which smokers of more than 1-1/2 packs per day of tobacco will be randomized to receive either placebo, 15, 30, or 60 mg (n=12 each) of oral beta-carotene daily for nine months following a 3 month placebo lead-in period. A concomitant, non-smoking control group will be randomized to receive either placebo or 30 mg. The second trial will utilize a blinded, randomized, crossover design. Twenty smokers and 20 non-smokers will receive 30mg of daily beta-carotene alone, or in combination with 400IU of vitamin E. After 5 months of treatment, subjects will be crossed over to receive the alternate regimen. Monthly plasma and buccal mucosal samples will be obtained for determination of beta-carotene, retinol, retinyl palmitate and, during the second trial, vitamin E. Skin and subcutaneous fat samples will be obtained on three occasions for retinoid and carotenoid concentrations. Breath ethane will be determined monthly as a marker of lipid peroxidation. Blood for immunologic markers will be obtained every three months. In addition, single dose studies have been incorporated into the study design to allow optimal determination of beta-carotene pharmacokinetic parameters (i.e. clearance, volume of distribution and half-life), both in smokers as compared to nonsmokers, and when administered in combination with another fat soluble vitamin. Rigorous dietary and compliance monitoring are incorporated throughout the chronic dose trials.
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