CHEMOPREVENTIVE ACTIVITY OF OLTIPRAZ AGAINST N-NITROSOBIS(2-OXOPROPYL)AMINE (BOP)-INDUCED DUCTAL PANCREATIC-CARCINOMA DEVELOPMENT AND EFFECTS ON SURVIVAL OF SYRIAN GOLDEN-HAMSTERS

The synthetic dithiolethione Oltipraz has marked cancer chemopreventiv e and phase II enzyme inducing activity in various animal carcinogenes is models, but has not been examined in any animal models of ductal pa ncreatic cancer relevant to the human disease. The chemopreventive pot ential of Oltipraz on pancreatic tumor incidence and multiplicity was examined in the N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pa ncreatic adenocarcinoma model in Syrian hamsters. Animals were maintai ned on control semipurified diets or semipurified diets containing 300 and 600 mg/kg Oltipraz beginning 2 weeks prior to BOP initiation and throughout the 26 week study. Oltipraz at 300 mg/kg had no effect on t he incidence or multiplicity of preneoplastic, neoplastic or metastati c lesions, while at 600 mg/kg dietary Oltipraz the incidence of pancre atic adenocarcinomas was reduced significantly (P less than or equal t o 0.05) compared to BOP-treated controls. Dietary Oltipraz at both dos es had a significant influence on reducing mortality and morbidity in tumor-bearing animals with metastatic disease. At 26 weeks, total hepa tic glutathione-S transferase (GST) activity and GST mu activity were elevated significantly in Oltipraz-treated animals, while total pancre atic GST activity was reduced, albeit not significantly. Serum lipase activity, a marker for pancreatic damage, exhibited a progressive decl ine in BOP-treated animals administered Oltipraz compared to BOP-treat ed controls at 12 weeks of the study; by week 26, lipase activity was comparable in all groups and reduced compared to activity at week 12. Positive nuclear immunostaining for the p53 tumor suppressor protein, a hallmark of human pancreatic cancer and a transient response to DNA damage, was observed in only a small percentage of BOP-induced adminis tration. Further chemoprevention and pharmacologic studies of Oltipraz in relevant animal models of ductal pancreatic cancer could provide a foundation for future studies in human populations at potential risk for pancreatic cancer.