INHIBITION OF ORNITHINE DECARBOXYLASE WITH 2-DIFLUOROMETHYLORNITHINE - REDUCED INCIDENCE OF DIMETHYLHYDRAZINE-INDUCED COLON TUMORS IN MICE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (6) , 2545-2549
Abstract
2-Difluoromethylornithine (DFMO) was administered to 1,2-dimethylhydrazine (DMH)-treated mice to reduce colonic polyamine levels and mucosal hyperplasia. Mice received 1% DFMO in drinking water throughout the experiment and were given injections of DMH (20 mg/kg) weekly for 28 wk. DFMO inactivated 93% of colonic ornithine decarboxylase activity. Although DMH treatment did not induce colonic ornithine decarboxylase activity by week 28, the putrescine content was increased 31% in DMH-treated mice (P < 0.01). Concurrent treatment with DFMO depressed putrescine content (42-63%) and spermidine content (27-38%), but it increased spermine content (18-22%). At week 28 of treatment with DMH alone, RNA content was increased 8.6% (P < 0.01), DNA content 10% (P < 0.01), DNA specific activity 24% (P < 0.01), and crypt depth 20% (P < 0.01), but not in mice receiving DMH and DFMO. At 28 wk, 13 of 17 mice (76%) treated with DMH alone had histologically confirmed colon cancers; of mice treated with DMH and DFMO, 2 of 18 (11%) had colonic tumors. Throughout the experiment, 50 colon cancers developed in 16 DMH-treated mice (mean, 3.12 tumors/mouse); 3 mice treated with DMH and DFMO developed 3 colon cancers total (P < 0.001). Reduction of colonic polyamine levels after DFMO treatment prevents proliferative changes induced by DMH and reduces the incidence of tumors.