LUNG-TUMOR INDUCTION IN A J MICE BY THE TOBACCO-SMOKE CARCINOGENS 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AND BENZO[A]PYRENE - A POTENTIALLY USEFUL MODEL FOR EVALUATION OF CHEMOPREVENTIVE AGENTS/

The purpose of this study was to establish a lung tumor model for the evaluation of chemopreventive agents against lung cancer in smokers, L ung tumor induction in A/J mice by 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone (NNK) and benzo[a]pyrene (BaP) was studied using protocols in which these two tobacco smoke carcinogens were given individually or in combination, Groups of female A/J mice were treated by either in tragastric gavage (i.g.) or by intraperitoneal injection (i.p.) with v arious doses of NNK and/or BaP for 8 consecutive weeks, The mice were killed either 9 or 19 weeks later and tumors of the lung and forestoma ch were counted, The i.g. route of administration proved to be more sa tisfactory than i.p. administration, because it avoided complications due to tumor formation at the injection site and associated mortality, A dose-response relationship for lung tumor induction by i.g. adminis tration of NNK and BaP in combination was established in the mice kill ed 9 or 19 weeks after completion of carcinogen treatment, The highest total doses of NNK and BaP (a total of 24 mu mol of each) induced mor e lung tumors than would have been expected by extrapolation from the lower doses, Comparisons of NNK and BaP given individually showed that BaP was more tumorigenic to the lung than NNK when given by the i.g. route; i.p. administrations of BaP were complicated by local tumor for mation and mortality. The most favorable dosing regimen of NNK and BaP for evaluation of chemopreventive agents appears to be a total dose o f 24 mu mol of each, administered in eight weekly subdoses i.g., with sacrifice 9 weeks after completion of dosing, This regimen induced 10. 5+/-4.4 lung adenomas/mouse. A combination of benzyl isothiocyanate an d phenethyl isothiocyanate, given 2 h prior to each gavage of NNK and BaP, was found to be an effective inhibitor of lung tumor formation, r educing the tumor multiplicity to 5.9+/-5.7 lung adenomas/mouse (P < 0 .001) and completely inhibiting forestomach tumor development, The res ults of this study provide a convenient model for assessing the effica cy of chemopreventive agents against lung cancer induction by tobacco smoke carcinogens.