Follow-up of tumor development in the colons of living rats and implications for chemoprevention trials: Assessment of aspirin-difluoromethylornithine combination

Abstract

We aimed to establish a reliable procedure allowing the follow-up of tumor development by computed tomographic (CT) colonography in an animal model of colon carcinogenesis in order to assess the chemopreventive efficacy of aspirin and difluoromethylornithine (DFMO) given in combination. Fischer rats received an intraperitoneal injection (25 mg/kg) of dimethylhydrazine (DMH) once a week for two weeks in order to initiate colon carcinogenesis. Five months after the last injection of DMH, a first CT colonography was performed and rats were then randomly separated into two groups (control and experimental). The experimental group received a 0.1% mixture of aspirin and DFMO in drinking water. CT colonography was performed at 6, 7 and 8 months. Data showed a precise correlation between location and size of tumors found at autopsy and those detected by CT colonography at 8 months. All tumors were also detected on the CT views obtained previously. Animals of the aspirin/DFMO group exhibited an inactivation of ornithine decarboxylase, a key enzyme in polyamine biosynthesis, and a two-fold reduction in the prostaglandin E2 content of the colonic mucosa (p<0.01). In rats with tumors at the start of the aspirin/DFMO treatment, a significant slow-down of tumor development was observed. In contrast, in rats where no tumors were detected at the start of the treatment, tumor formation was inhibited. Our data show that CT colonography represents a reliable method to assess in a living animal the efficacy of chemopreventive agents.