DNA methyl-adduct dosimetry and O6-alkylguanine-DNA alkyl transferase activity determinations in rat mammary carcinogenesis by procarbazine and N-methylnitrosourea

The metabolism of the carcinogenic antitumor drug procarbazine (PCZ) is complex with the ultimate production, among other metabolites, of a methyldiazonium ion which is also the ultimate carcinogenic species of the DNA-methylating N-nitroso compounds including N-methylnitrosourea (MNU). This suggests a similar mechanism of carcinogenic action. Following a single oral dose of 14C]PCZ (50 mg/rat) to 50 day old female Sprague-Dawley rats under the reported conditions of mammary gland carcinogenicity, the DNA adducts 7-methylguanine (7-meG) and O6-methylguanine (O6-meG) were determined in target (mammary gland) and non-target organs. The degree of DNA methylation was similar in all the organs considered. In the mammary gland, lung, spleen, small intestine and stomach the O6-meG/7-meG ratio was close to 0.11. At a lower dose of PCZ (26 mg/rat), the levels of 7-meG in the tissues were 40-60% of those produced by the higher dose. Eighty percent of the rats given the higher dose versus 37% of those given the lower dose developed mammary tumors after 20 weeks. With the higher dose of MNU (50 mg/kg body wt) DNA methylation was more or less uniform in all the organs including the mammary gland, with slightly greater yields in the liver. At a lower MNU dose (25 mg/kg) the levels of 7-meG were 40-48% of those produced by the higher dose. Fifty seven percent of the rats given the higher dose versus 21% of the animals given the lower dose developed mammary gland tumors after 20 weeks. On a mol/kg body wt basis, PCZ was approximately 5-times less active than MNU in the production of 7-meG in mammary gland but only approximately 2-times less active than MNU in the production of mammary gland tumors. The O6-alkylguanine-DNA alkyltransferase (AGT) levels in the liver, kidney, spleen and lung of PCZ or MNU treated rats were approximately 9-28% (expressed relative to protein content) and 10-33% (expressed relative to homogenate DNA content) of those in the corresponding organs of the saline-treated controls. However, the AGT levels of the mammary gland and brain were in the range of 45-61% (expressed relative to protein content) and 39-54% (expressed relative to homogenate DNA content) of those of the saline-treated controls. Also the mammary gland of the 50 day old female rats has the lowest AGT activity (expressed relative to DNA content).(ABSTRACT TRUNCATED AT 400 WORDS)