EFFECT OF ALPHA-DIFLUOROMETHYLORNITHINE ON RECTAL MUCOSAL LEVELS OF POLYAMINES IN A RANDOMIZED, DOUBLE-BLINDED TRIAL FOR COLON-CANCER PREVENTION

Background: Polyamines (e,g., putrescine, spermidine, and spermine) ar e required for optimal cell growth. Inhibition of polyamine synthesis suppresses carcinogen-induced epithelial cancers, including colon canc er, in animal models, In a short-term phase IIa trial, we determined t hat low doses of -difluoromethylornithine (DFMO), an inhibitor of orni thine decarboxylase tan enzyme involved in polyamine synthesis), reduc ed the polyamine content of normal-appearing rectal mucose of subjects with a prior history of resected colon polyps. Zn a follow-up study, We have attempted to determine the lowest dose of DFMO that can suppre ss the polyamine content of rectal mucosa over a course of a year with no or minimal side effects, Methods: participants were randomly assig ned to daily oral treatment With a placebo or one of three doses (0.07 5, 0.20, or 0.40 g/m(2)) of DFMO, Baseline and serial determinations o f polyamine levels ire rectal mucosa and extensive symptom monitoring (including audiometric measurements, since DFMO causes some reversible hearing loss at higher doses) were performed over a 15-month period. Results: DFMO treatment reduced putrescine Bevels in a dose-dependent manner, Following 6 months of treatment, doses of 0.20 and 0.40 g/m2 p er day reduced putrescine levels to approximately 34% and 10%, respect ively, of those observed in the placebo group, Smaller decreases were seem in spermidine levels and spermidine:spermine ratios. Polyamine le vels increased toward baseline values after discontinuation of DFMO. A lthough there were no statistically significant differences among the dose groups with respect to clinically important shifts in audiometric thresholds and nonaudiologic side effects, statistically significant higher dropout and discontinuation rates were observed in the highest dose group, Conclusions: Polyamine levels in rectal mucosa can he cont inuously suppressed by daily oral doses of DFMO that produce few or no side effects, a dose of 0.20 g/m(2) can be used safely in chemopreven tion phase IIb or single-agent phase III chemoprevention trials.