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The Significance of DNA Damage, Its Repair and Cell Proliferation during Carcinogen Treatment in the Initiation of Pancreatic Cancer in the Hamster Model ¹

Departments of Pathology [V. S] and Pharmacology [D. M. K.] and the Cancer Center [D. M. K.]. Northwestern University Medical School, Chicago, Illinois 60611

N-Nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) is a complete pancreatic carcinogen in female hamsters at a dose of 210 mg/kg given via an Alzet 2001 pump implanted s.c. Ultimate carcinogenic metabolites of HPOP target DNA to yield 7- and O⁶-methylguanines (7-mGua, O⁶-mGua) and 7- and O⁶-hydroxypropylguanines (7-HpGua, O⁶-HpGua). During continuous administration of HPOP, levels of DNA alkylation increase linearly with time of exposure and reach a maximum at the end of treatment. Such levels are markedly lower in pancreas or in its component duct or acinar cells than in liver or in other extrahepatic organs examined, indicating that the organotropy of HPOP does not directly correlate to its extent of activation by various tissues. After continuous treatment with HPOP, all major DNA adducts with the exception of 7-mGua in liver are repaired at rates slower than those measured after a single injection of the carcinogen. Half-lives for the repair of O⁶-mGua are 240 h in liver and considerably longer in extrahepatic tissues. Half-lives for the removal of 7-mGua are 46, 55, 72, and 96 h in liver, kidney, lung, and pancreas; while respective values for 7-HpGua are 216, 216, 132, and 140 h. No significant repair is observed for O⁶-HpGua for at least 8 days. The above differences in half-lives result in the gradual increase of 7-HpGua and O⁶-HpGua relative to their methyl counterparts. DNA synthesis progressively increases during HPOP infusion in all the tissues examined, and reaches maximum levels 3 to 4 days after termination of treatment. In pancreas, such levels are up to 5 times greater in HPOP treated animals than in controls. The increase in DNA synthesis during carcinogen treatment is due to the greater number of cells entering S phase rather than to an increase in the rate of proliferation of a certain population of cells. The mitogenic effect of HPOP in the pancreas and the persistence of highly promutagenic hydroxypropyl adducts are postulated to contribute to the initiation of pancreatic cancer in the hamster model.

¹ Supported by ACS-Illinois Grant 07-91.

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

Received 1/ 4/93. Accepted 4/ 9/93.

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