α-Difluoromethylornithine-induced Inhibition of Growth of Autochthonous Experimental Colonic Tumors Produced by Azoxymethane in Male F344 Rats

Ornithine decarboxylase, the first regulatory enzyme in polyamine biosynthesis, is inhibited by α-difluoromethylornithine (DFMO), a specific enzyme-activated irreversible inhibitor. DFMO has been shown previously to inhibit experimental colonic tumorigenesis in rodents given the large bowel carcinogen azoxymethane or dimethylhydrazine. Therefore, we assessed the effects of DFMO on growth of established autochthonous experimental colonic tumors. Ten-wk-old male F344 rats were given 10 weekly s.c. injections of azoxymethane, 10 mg/kg. Starting 5 wk after the last dose, colonoscopy to the splenic flexure was performed weekly with a pediatric fiberoptic bronchoscope. When a tumor was visualized, its growth was assessed by computer image analysis of weekly colonoscopic photographs which included a scale. After two measurements for baseline tumor growth, the tumor-bearing rats were assigned in predetermined alternating sequence to the DFMO group (n = 26) or control group (n = 28). DFMO, 30 mg/ml (3%), was given in drinking water for 4 wk, resulting in mean weekly intake of 16 ± 1 (SE) to 18 ± 1 mg of DFMO/g of body weight. Control rats were pair-fed, resulting in reduced body weights comparable to DFMO rats. DFMO dramatically inhibited tumor growth, beginning in the first week of administration: Mean tumor volume of DFMO rats reached only 7.0 ± 2.0 mm³ compared with 17.4 ± 3.2 mm³ in controls (P < 0.02); and tumors in three DFMO rats disappeared. Mean change in tumor volume in DFMO rats was less than controls during all 4 wk of administration, although there was a suggestion of escape from DFMO suppression of tumor growth in the last 2 wk. At necropsy, tumor ornithine decarboxylase activity was 115 ± 22 pmol/h/mg of protein in DFMO rats as compared with 842 ± 576 in controls. There was a suggestion of greater tumor desmoplasia in DFMO rats, but tumor differentiation, depth of invasion, inflammation, and labeling index with tritiated thymidine showed no statistically significant differences between the DFMO and control groups. Our findings suggest that (a) ornithine decarboxylase plays a key role in growth of autochthonous experimental colonic tumors, and (b) DFMO may have potential for chemotherapy and chemoprophylaxis of colorectal neoplasms in human beings.