A colon cancer chemoprevention trial is proposed utilizing difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC), to modulate odc and related enzymes and markers of colonic mucosal proliferation. We proposed to utilize colonic mucosal ODC as an intermediate endpoint which can be modulated by the administration of chemopreventive agents, including DFMO. We also proposed to determine the potential toxicity of different doses of DFMO, and to evaluate the biologic and/or clinical effects of decreased mucosal proliferation and the possible associated reduction in neoplastic transformation and progression of the colonic polyps. We have completed pilot studies in 5 patients with familial polyposis who were given DFMO for 7 days. Mucosal ODC was inhibited, with associated decreases in mucosal proliferative activity as measured by thymidine labeling. Patient acceptance and compliance was 100% and no toxicities were found. Our proposed Phase I studies will be performed in up to 40 patients. Each will complete 6 cycles of 21 days on DFMO and 7 days off DFMO, with weekly monitoring of potential toxicity. Monitoring of colonic mucosal ODC and proliferative activity will be done at monthly intervals, with provision for stopping DFMO or reducing its dose for efficacy and for toxicity. The doses used will be decreased to find the minimal effective dose of DFMO needed for an approximately 50% reduction in ODC activity from levels associated with high cancer risk to levels found in normal controls (i,e., <2 nmol/mg/h). Patients will be recruited with the assistance of the Metropolitan Detroit Cancer Surveillance System. If results are positive a full scale double-blind randomized clinical trial will be done using the optimal DFMO dose and schedule, and the ODC activity, size, distribution, and histologic dysplasia of the polyps and their progression to cancer will be monitored.
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| Moshier, J A; Osborne, D L; Skunca, M et al. (1992) Multiple promoter elements govern expression of the human ornithine decarboxylase gene in colon carcinoma cells. Nucleic Acids Res 20:2581-90 |
