INHIBITION OF ORNITHINE DECARBOXYLASE BY ORAL COMPOUNDS

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The overall objective of this proposal is to develop, through a rational approach, an ideal dose and administration schedule of a drug which can be administered orally in a prospective chemo-preventive trial in patients at high risk of developing malignant disease. The observation that forms the basis of this proposal is that the induction of mouse epidermal ornithine decarboxylase (ODC) by a phorbol ester tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA) is correlated to the promotion of skin tumor formation in mice. Evidence indicates that the induction of ODC activity is an essential property of tumor promoters. Topical or systemic agents that prevent the induction of ODC (eg. retinoids and prostaglandin synthesis inhibitors) or inhibit the action of ODC (difluoromethylornithine, DFMO) can prevent skin tumor promotion in mice. In mice, when administered orally, these antipromoters inhibit TPA caused ODC activity in vitro in 3 mm punch biopsies of mouse skin. These observations have now been extended to human skin. Preliminary results indicate that ODC can be induced by TPA in incubated human skin punch biopsies and that in vitro retinoic acid inhibits TPA caused ODC induction in human skin. Further plans are: 1) to define intra-subject and inter-subject variability of epidermal ODC activity and inducibility by TPA; 2) to demonstrate in humans the ability of orally administered nontoxic substances (eg., aspirin, retinoids, or DFMO) to preclude TPA-caused increased ODC activity; 3) to determine an ideal dose and dose schedule for such a substance; and 4) to propose a prospective randomized chemoprevention drug trial in a group of patients with high risk of developing cancer. Fasting volunteers will be used to determine TPA-induced ODC activity in vitro in 3 mm skin punch biopsy specimens. To determine appropriate human chemopreventive agents, doses, and dose schedules, punch biopsies will be obtained for in vitro induction of ODC by TPA both before and after oral medications are administered. This in vitro human assay system will help determine the requisite doses and dose schedules of certain chemopreventive agents for use in future human chemoprevention trials.