A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF LOW-DOSE ALPHA-DIFLUOROMETHYLORNITHINE IN INDIVIDUALS AT RISK FOR COLORECTAL-CANCER

DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC), th e key enzyme in mammalian polyamine biosynthesis, The goal of this stu dy was to determine the effects of DFMO 0.5 g/m(2)/day as a single ora l dose on polyamine and ODC levels in rectal, rectosigmoidal, and ceca l colonic mucosae of individuals at risk for colon cancer because of a personal history of adenomatous polyps of the colon or a family histo ry of colon cancer in at least one first-degree relative, A second goa l was to determine toxicity of this treatment given over 1 year. Forty -five randomized subjects had a flexible sigmoidoscopy with no prepara tion and a colonoscopy after lavage preparation at baseline, a sigmoid oscopy with no preparation after 3 months, and both procedures (as at baseline) after 12 months, with mucosal biopsies taken from the rectos igmoid area (sigmoidoscopy) or rectal and cecal areas (colonoscopy) fo r evaluations of ODC and polyamine levels, Significantly decreased lev els of putrescine and spermidine were found in rectosigmoid colonic mu cosae of DFMO-treated (n = 24) compared with placebo (n = 21) subjects at 3 months (P = 0.03 and 0.04) and 12 months (P = 0.005, P = 0.004), Similar trends, none reaching statistical significance, were found fo r individual polyamine levels in rectal and; cecal mucosae, No signifi cant differences in ODC levels were detected marginally. There was evi dence of global suppression of ODC and polyamine levels in the treatme nt group (P = 0.035), Three DFMO recipients (12.5%) developed clinical ly noticeable and audiologically demonstrated hearing loss, which was reversible and attributed to DFMO after 3 months (two subjects) and 12 months (one subject). The tissue polyamine changes demonstrated in th is study are consistent with findings in other studies in colon and ot her tissues. The ototoxicity findings here suggest that investigation of other DFMO schedules, such as ones with a drug ''holiday,'' will be a necessary step before Phase III chemoprevention studies can be purs ued.