DOSE DE-ESCALATION CHEMOPREVENTION TRIAL OF ALPHA-DIFLUOROMETHYLORNITHINE IN PATIENTS WITH COLON POLYPS

Background: alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models. In these animal mode ls, DFMO has been especially active in preventing carcinogen-induced e pithelial cancers, including those of the skin, colon, breast, and uri nary bladder. Although DFMO is known to exert its diverse biological e ffects by suppressing intracellular pools of the polyamines putrescine and spermidine, the precise mechanism by which polyamine depletion, i nduced by DFMO, suppresses carcinogenesis is unknown. Purpose: The spe cific aim of our study was to determine the lowest dose of DFMO that w ould deplete target tissue (colorectal mucosa) levels of these polyami nes in humans who had undergone prior removal of colon polyps while pr oducing minimal toxic effects. Methods: A dose de-escalation chemoprev ention trial of DFMO was conducted in 111 patients (36 female and 75 m ale) who were in generally good health, aged 39-79, and who had underg one colonoscopy for surgical removal of an adenomatous colon polyp gre ater than 3 mm within 5 years prior to entering the study. Groups of p atients (12-20 patients per group) were orally treated with single, da ily doses of DFMO ranging from 3.0 to 0.1 g/m(2) for 4 weeks (28 days) . Prior to initiation of DFMO treatment and at the end of treatment, s ix colorectal biopsy specimens were collected from each patient, along with serum samples. All biopsies were performed between 9 AM and noon to avoid possible effects of diurnal variations in laboratory end poi nts. Samples for analysis of plasma DFMO levels were also collected du ring this time period on the day after the last day of drug administra tion. Results: DFMO caused a decrease in both putrescine content and t he ratio of spermidine to spermine for all dose groups down to 0.25 g/ m(2). Both putrescine content and the ratio of spermidine to spermine and changes in these parameters as a function of DFMO treatment decrea sed as a function of donor age. None of the 30 patients receiving eith er 0.25 or 0.5 g/m(2) experienced any clinical ototoxicity in this tri al, Conclusions: DFMO is both safe and effective in reducing colorecta l mucosal polyamine contents when it is administered orally to patient s at doses as low as 0.25 g/m(2) for 28 days. No ototoxicity was obser ved at doses up to twice this amount. Implications: If DFMO is also fo und to be effective in suppressing polyamine contents in other target tissues, it may be useful in preventing a wide range of human epitheli al cancers, including those of the prostate and breast.