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Orotic Acid Enhancement of Preneoplastic and Neoplastic Lesions Induced in the Pancreas and Liver of Hamsters by N-Nitroso(2-hydroxypropyl) (2-oxopropyl)amine¹

Departments of Neurology [D. K.] and Pathology [J. A-S.], The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9036

The effect of dietary orotic acid (OA) in liver-pancreas carcinogenesis induced in female Syrian hamsters by N-Nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) was evaluated. All animals infused with the carcinogen received the same doses. Results of the control group which received no OA or carcinogen were compared with the results of: (a) hamsters treated with HPOP and fed a regular 20% protein synthetic diet (group 1); (b) hamsters fed the OA diet for a brief time period during initiation with the carcinogen (group 2); and (c) hamsters in which OA was administered after carcinogen infusion for life (group 3).

All animals of the control group were normal at autopsy, while those in group 1 (HPOP alone) revealed the spectrum of lesions accepted as classical in the multistep hyperplasia-dysplasia-carcinoma in situ (CIS) sequence of carcinogenesis. Results of group 2, in light of group 1, revealed an increased incidence of the following lesions in the common pancreatic duct: dilatation, 2.5 times; flat and papillary hyperplasia, 2 times; and dysplasia (atypical hyperplasia), 12 times. No significant increase of CIS and invasive cancer in the body and tall of the pancreas was observed; in addition, the incidence, nature, and location of pancreatic adenocarcinomas were not affected. Yet, the effect of OA administered after carcinogen infusion (group 3) when compared to group 1 seemed to enhance a further increase in the incidence of practically all lesions throughout the pancreas. An obvious overall step-up incidence along the multistep hyperplasiadysplasia-CIS-invasive cancer process in the pancreas was observed. The increase in incidence of flat, papillary, and atypia of the epithelium of the common pancreatic duct in group 3 was mild compared to that found in the same duct of group 2, but the increase in incidence of these same three lesions when found in the main ducts was marked: flat hyperplasia, 3-fold; papillary hyperplasia, 2.5-fold; atypical hyperplasia, 3-fold. The increase in incidence of CIS in this group was 5-fold and papillary adenocarcinomas, 3-fold, when compared to 5% found in groups 1 and 2. Hepatic malignancies (cholangiocarcinomas) occurred in 6% of the cases in group 3 compared to none in group 2; the incidence of malignancy in the gallbladder was the same in groups 2 and 3 but three times greater than that in group 1. Our results suggest that not all ductal cells of the pancreas respond to OA promotion, which implies that various pancreatic tumors in the hamster, and by extrapolation, in humans, may have different etiologies.

¹ This work was supported by NCI Grant CA-42983 and ACS-Illinois Grant 09-91.

² To whom requests for reprints should be addressed, at Department of Neurology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9036.

Received 4/ 5/94. Accepted 8/17/94.