α-Difluoromethylornithine Inhibits N-Nitrosomethylbenzylamine-induced Esophageal Carcinogenesis in Zinc-deficient Rats: Effects on Esophageal Cell Proliferation and Apoptosis

摘要: Sustained, increased cell proliferation induced by dietary zinc deficiency in rats plays a critical role esophageal carcinogenesis. It is the determining factor that converts an otherwise nontumorigenic dose of N -nitrosomethylbenzylamine (NMBA) into highly tumorigenic one. We studied whether and susceptibility to NMBA-induced carcinogenesis can be inhibited α-difluoromethylornithine (DFMO), enzyme-activated, irreversible inhibitor ornithine decarboxylase (the first enzyme polyamine synthesis). Weanling were divided four groups: Zn+/DFMO-, Zn+/DFMO+, Zn-/DFMO-, Zn-/DFMO+. They fed ad libitum either zinc-sufficient (Zn+, 75 ppm zinc) or zinc-deficient (Zn-, 4 diet given deionized water (DFMO-) 1% DFMO (DFMO+). After 5 weeks, 5–19 animals from each group sacrificed after vivo 5-bromo-2′-deoxyuridine labeling detect cells S phase. The remaining single intragastric NMBA at 2 mg/kg 12 weeks later for tumor incidence analysis. At week 5, treatment greatly decreased (by 48–82%) levels putrescine spermidine rat esophagus, colon, liver, irrespective intake. deficiency, as measured index, number labeled cells, total was substantially reduced DFMO. This accompanied increase rate apoptosis. In addition, expression bax protein, apoptosis accelerator, markedly stronger esophagi Zn-/DFMO+ showed apoptosis, whereas bcl-2 , only seen proliferative, esophagus (Zn-/DFMO-). dosing, tumors 80 4% rats. Our data effectively animals. results also indicate mechanism(s) whereby brings about inhibition induction. These findings support chemopreventive agent.