THE SIGNIFICANCE OF DNA-DAMAGE, ITS REPAIR AND CELL-PROLIFERATION DURING CARCINOGEN TREATMENT IN THE INITIATION OF PANCREATIC-CANCER IN THEHAMSTER MODEL

N-Nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) is a complete panc reatic carcinogen in female hamsters at a dose of 2 1 0 mg/kg given vi a 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 conti nuous administration of HPOP, levels of DNA alkylation increase linear ly 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 treatme nt with HPOP, all major DNA adducts with the exception of 7-mGua in li ver are repaired at rates slower than those measured after a single in jection of the carcinogen. Half-lives for the repair of O6-mGua are 24 0 h in liver and considerably longer in extrahepatic tissues, Half-liv es 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 a t least 8 days. The above differences in half-lives result in the grad ual increase of 7-HpGua and O6-HpGua relative to their methyl counterp arts. DNA synthesis progressively increases during HPOP infusion in al l the tissues examined, and reaches maximum levels 3 to 4 days after t ermination of treatment. In pancreas, such levels are up to 5 times gr eater in HPOP treated animals than in controls. The increase in DNA sy nthesis during carcinogen treatment is due to the greater number of ce lls entering S phase rather than to an increase in the rate of prolife ration of a certain population of cells. The mitogenic effect of HPOP in the pancreas and the persistence of highly promutagenic hydroxyprop yl adducts are postulated to contribute to the initiation of pancreati c cancer in the hamster model.