Regeneration of Syrian Golden Hamster Pancreas and Covalent Binding of N-Nitroso-2,6-[³H]dimethylmorpholine

The Syrian golden hamster is a potentially useful model for studies of chemically induced pancreatic adenocarcinoma. In an effort to refine the model so its sensitivity to carcinogen can be enhanced such that dose and latent period are decreased and tumor yield increased, experiments were undertaken to induce pancreatic regeneration in the hamster. Random-bred male hamsters given eight daily i.p. injections of DL-ethionine (500 mg/kg body weight) in 0.9% NaCl solution while on a methionine-deficient diet developed pancreatic injury. This was characterized by a progressive decrease (72%) in wet weight of pancreas accompanied by acinar cell atrophy and necrosis. Pancreatic regeneration initiated on the ninth day by a single i.p. injection of L-methionine and return to a full amino acid diet led to a gradual increase in wet weight of pancreas, reaching 80% of control pancreas weight at 8 days later and full restitution by the 17th day. Mitotic activity, localized largely in acinar cells, rose from a total absence of mitoses on the eighth day before initiation of regeneration to a peak value of 16.8 ± 5.0 (S.E.) per 1000 cells 72 hr later, following which it decreased steadily to a level of 2.8 ±1.5 per 1000 cells at 192 hr. Islet and ductal epithelium showed peak indices of only 1.8 ± 0.86 and 1.4 ± 0.6, respectively, at 72 hr. The mitotic index of control animals was 0.84 ± 0.76 per 1000 cells. Uptake of [³H]thymidine limited to acinar cell nuclei was evident 12 hr after initiation of regeneration (22 ± 5.5 per 1000 nuclei), reached a peak value of 224 ± 25 per 1000 nuclei at 60 hr, and decreased to 32 ± 26 per 1000 nuclei at 192 hr. Pancreatic slices from regenerating (60 hr) and normal pancreas were incubated in vitro with 0.1 mM N-nitroso-2, 6-[³H]di-methylmorpholine for 90 min. Regenerating pancreas showed increased covalent binding of carcinogen to DNA (21-fold), RNA (20-fold), and protein (3.7-fold) as compared to binding observed in normal nonregenerating pancreas. In contrast to the other rodent models of pancreatic regeneration, the hamster responds more rapidly and intensely, suggesting that pancreatic regeneration may be a useful approach toward development of a limited dose schedule for pancreatic carcinogenesis in this species.