Chemoprevention by N-acetylcysteine of urethane-induced clastogenicity and lung tumors in mice.

Abstract

A major goal in pre-clinical cancer chemoprevention research is to assess the predictive value of intermediate biomarker modulation towards tumor prevention. With this aim, BALB/c mice were treated with 10 daily i.p. injections of urethane (ethyl carbamate), each of 400 mg/kg body weight. Groups of mice received with drinking water either a drug containing the thiol N-acetylcysteine (NAC), at 0.1 or 0.5 g/kg body weight, or its excipient, starting 27 days before the first injection of the carcinogen until the end of the experiment. Out of the 30 mice, 10 per group were identified and individually monitored for 8 sequential times in order to assess the course of micronucleated normochromatic erythrocytes in peripheral blood. This systemic genotoxicity biomarker increased during the 10-day period of treatment with urethane, reached a peak 2 to 6 days after the last injection, and was still significantly higher than the baseline after 10 additional days. Clastogenicity was significantly inhibited by NAC, with a dose-related effect, but not by the drug excipient. As evaluated 4 months after the first injection of urethane, most mice developed lung tumors, whose multiplicity was not affected by the drug excipient but was significantly decreased in the presence of NAC. Correlation between the frequency of micronucleated normochromatic erythrocytes at peak levels and lung-tumor multiplicity was highly significant when evaluated in the context of all 40 mice undergoing cytogenetic analyses (r = 0.561, p = 0.0002). It was similarly high, but did not reach the significance threshold, within each treatment group, due to the lower number of animals and some deviations from the regression line. Therefore, the prediction of lung-tumor yield based on the intensity of the early genotoxicity biomarker is justified when formulated within a sufficiently large group of animals, but is not absolute at individual level.