Supplemental Effect of 1,2-Dimethylhydrazine on Methylazoxymethanol Acetate-induced Colon Carcinogenesis in Rats; Effect of α-difluoromethylornithine on the Progression of Tumorigenesis

In the present study, establishment of a rat model for progression in the large bowel carcinogenesis by combined exposure of methylazoxymethanol (MAM) acetate and 1,2-dimethylhydrazine (DMH) was tried, and the modifying effect of α-difluoromethylornithine (DFMO), a chemopreventive agent, was examined in this model. A total of 200 F344 male rats were divided into 8 groups. At 6 weeks of age, the rats of Groups 1 (30 rats), 2 (30 rats), 3 (30 rats), and 4 (30 rats) were given i.p. injections of MAM acetate (20 mg/kg body weight) once a week for 3 weeks. Sixteen weeks after the first injection of MAM acetate, the rats of Groups 3, 4, 5 (20 rats), and 6 (20 rats) received s.c. injections of DMH (20 mg/kg body weight) once a week for 10 weeks. Fifteen weeks after the first treatment of MAN acetate, the rats of Groups 2, 4, 6, and 7 (20 rats) were exposed to DFMO in drinking water at a concentration of 0.1%. Group 8 (20 rats) was served as an untreated control. The incidence of colon cancer of Group 3 (MAM→DMH, 62%) was higher than that of Group 1 (MAM alone, 31%, P<0.05). The numbers of intestinal cancer with a high grade of atypia per rat (0.69 ± 0.79) and a deeper invasion in the wall per rat (0.65 ± 0.69) of Group 3 were significantly larger than those of Group 1 (0.31 ± 0.47, P<0.05; 0.24 ± 0.44, P<0.01). The incidence and multiplicity of colon cancer of Groups 2 (MAM→DFMO, 21%, 0.25 ± 0.52) and 4 (MAM→DMH + DFMO, 39%, 0.39 ± 0.50) were less than those of Groups 1 (31%, 0.45 ± 0.87) and 3 (62%, 0.77 ± 0.76). Concerning the number of intestinal cancer with a high grade of atypia or a deeper invasion in the gut wall, however, no significant differences were recognized. Only the rats of Groups 3 and 4 had metastatic cancer to lymph nodes or other organs (Group 3, 31%; Group 4, 29%). These results suggest that the combination of MAM acetate and DMH could be effective as a progression model for colorectal carcinogenesis. DFMO did not show clear effects on progression in colon carcinogenesis, although the agent had an inhibitory potential on the development of tumors.

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