Chemopreventive activity of Oltipraz against N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic carcinoma development and effects on survival of Syrian golden hamsters

Abstract

The synthetic dithiolethione Oltipraz has marked cancer chemopreventive and phase II enzyme inducing activity in various animal carcinogenesis models, but has not been examined in any animal models of ductal pancreatic cancer relevant to the human disease. The chemopreventive potential of Oltipraz on pancreatic tumor incidence and multiplicity was examined in the N-nitrosobis(2-oxopropyl)-amine (BOP)-induced ductal pancreatic adenocarcinoma model in Syrian hamsters. Animals were maintained 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 the incidence or multiplicity of preneoplastic, neoplastic or metastatic lesions, while at 600 mg/kg dietary Oltipraz the incidence of pancreatic adenocarcinomas was reduced significantly (P ≦ 0.05) compared to BOP-treated controls. Dietary Oltipraz at both doses had a significant influence on reducing mortality and morbidity in tumor-bearing animals with metastatic disease. At 26 weeks, total hepatic glutathione-S transferase (GST) activity and GST mu activity were elevated significantly in Oltipraz-treated animals, while total pancreatic GST activity was reduced, albeit not significantly. Serum lipase activity, a marker for pancreatic damage, exhibited a progressive decline in BOP-treated animals administered Oltipraz compared to BOP-treated 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 pancreatic lesions and was not influenced Oltipraz administration. 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.