Herman S. Lilja

Pancreatic carcinoma in azaserine-treated rats: Induction, classification and dietary modulation of incidence

Pancreatic carcinomas have been induced in Wistar and W/LEW rats by administration of total azaserine doses of 150–520 mg/kg by injection or oral routes over periods of 5–52 weeks. The latent period for development of invasive carcinomas was 1–2 years, but focal abnormalities in acinar cells appear earlier. The incidence of carcinomas varied with total dose, route, and schedule of azaserine administration. The spectrum of histologic patterns of the carcinomas included well and poorly differentiated acinar cell, ductlike, and undifferentiated carcinomas. Rats fed a purified diet developed more pancreatic neoplasms than rats fed a commercial laboratory chow. Selective feeding of these diets during the administration of carcinogen and following completion of carcinogen treatment indicated that the inhibitory effect of chow on pancreatic carcinogenesis was exerted during the postinitiation phase. Supplementation of diet with 0.025% retinyl acetate during the postinitiation phase also inhibited the progression of azaserine‐induced lesions in the pancreas.

Transplantation of azaserine-induced carcinomas of pancreas in rats*

Two pancreatic adenocarcinomas which had been induced in Wistar/Lewis rats by azaserine treatment were transplanted into rats of the same strain by subcutaneous and intraperitoneal injection of minced tumor. Subsequently, we have serially transplanted into non-radiated recipients. Transplanted tumors have maintained evidence of acinar cell differentiation including the presence of zymogen granules in tumors studied by electron microscopy, and of lipase, amylase and trypsin activity in the supernatant of tumor homogenates. Histologically, the tumors vary from poorly differentiated solid carcinomas to well differentiated variants which form acini. Transplanted tumors are locally invasive and have metastasized to lung and liver in some recipients.

Persistence of DNA damage in rat pancreas following administration of three carcinogens and/or mutagens.

Abstract Alkaline sucrose gradients were used to detect and follow the persistence of DNA damage in pancreas and liver of Wistar and Wistar/Lewis rats after i.p. injection of azaserine, N δ -( N -methyl- N -nitroso-carbamyl)-L-ornithine (MNCO) or neutral red. The results were compared with the mutagenicity and carcinogenicity of each compound. Damaged DNA was present in pancreas 1 h after administration of azaserine (10 mg/kg), a pancreatic and liver carcinogen, and damage persisted in both pancreas and liver longer than a week. More extensive damage to pancreatic and liver DNA was detectable 1 week following either 6 weeks or 6 months of weekly azaserine injections than was detectable 1 week after a single injection. Damage to pancreatic DNA was detected in rats 1 h after treatment with the pancreatic carcinogen MNCO (72 or 218 mg/kg). Pancreatic DNA damage was not apparent 1 week after MNCO, 72 mg/kg, but was detectable 1 week after 218 mg/kg. Significant pancreatic DNA damage was detected 1 week after 6 weeks or 6 months of weekly MNCO injections, 72 mg/kg. Damage to liver DNA was not detectable at either 72 or 218 mg/kg whether administered once or weekly in the above protocols. One hour following injection of neutral red, 96 mg/kg, DNA damage was present in pancreas and liver, but at 1 week no damaged DNA was apparent in either tissue. Limited DNA damage was detectable in liver but not in pancreas 1 week following a toxic dose of neutral red, 288 mg/kg. Persistent DNA damage was also detectable in liver but not in pancreas after 6 weekly injections of neutral red, 96 mg/kg. The results indicate that relative persistence of DNA damage may be an accurate indication of the organotropic carcinogenic potential of azaserine, MNCO and neutral red administered at non-toxic dose levels.

Studies of DNA damage in rat pancreas and liver by 6-diazo-5-oxo-L-norleucine, ethyl diazoacetate and azaserine

One hour following intraperitoneal injection of the pancreatic and liver carcinogen azaserine, 10 mg/kg (0.06 mmol/kg), DNA damage is present in both pancreas and liver of Wistar/Lewis rats as determined with alkaline sucrose gradients. Single injections (0.06 mmol/kg) of either of 2 structural analogues of azaserine, 6-diazo-5-oxo-L-norleucine (DON) and ethyl diazoacetate (EDA), do not damage pancreatic or liver DNA. EDA administered at 0.5 mmol/kg damages liver DNA, but not pancreatic DNA. Total radioactivity in pancreas and liver of Wistar rats 1 h after intravenous injection of [14C]azaserine, (10 microCi/kg), is 2.8 and 1.3 times respectively, the level of 14C-activity in pancreas and liver following injection [14C]EDA. Three to four times as much [14C]EDA localizes in the liver of Wistar rats as in the pancreas. Azaserine (0.06 mmol/kg weekly for 6 weeks) induces atypical acinar cell nodules (AACN) in pancreas of Wistar/Lewis rats. DON (0.06 mmol/kg weekly for 6 weeks) induces an elevated incidence, but low number of AACN in pancreas. EDA (0.10 mmol/kg weekly for 6 weeks) does not induce pancreatic AACN.

Response of the Syrian golden hamster to a nitrosourea amino acid carcinogen

Syrian golden hamsters were treated with N delta-(N-methyl-N-nitrosocarbamoyl)-L-ornithine (MNCO), a nitrosourea amino acid, which has induced a high incidence of breast, kidney and skin neoplasms and a low incidence of pancreatic carcinoma in rats. MNCO induced a few breast and skin carcinomas, and a high incidence of foci of atypical acinar cells and of focal ductular abnormalities in the exocrine pancreas. The latter were similar to lesions observed in rats treated with MNCO. MNCO was less toxic and less effective as a carcinogen in hamster than in the rat.