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 < or = 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.