Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice

Fewer lung adenomas were induced by urethan in BALB/cBy mice than in the A/J or SWR/J mouse strains. When BALB mice were crossed with either of these more sensitive strains the response of the progeny to urethan was most easily explained by a single gene which regulates susceptibility, with the more resistant phenotype behaving as a dominant trait. C56BL/6J mice were more resistant to adenoma induction than were BALB mice; progeny obtained when these two strains were crossed resembled the BALB susceptibility phenotype. As an approach to understanding the mechanism of action of this gene, agents that modulate adenoma initiation and tumor promotion were tested in BALB mice and other strains. The number of adenomas in BALB mice were increased severalfold by multiple urethan injections, which presumably affect initiation, and by the use of butylated o-hydroxytoulene as a promoting agent. Tumor incidence in A-mice was increased 50% by each treatment; neither procedure caused tumors to appear in the resistant DBA/2J, C3H/-21BG, or C57BL/6J strains. No relationship was observed between the strain dependency of the lethal effects of multiple injections of these agents and the relative susceptibilities of these strains to adenoma induction. The role of certain host factors in the regulation of tumor susceptibility was also tested. Homozygosity for the beige (bg) mutation had no effect on tumor numbers in C57 mice, suggesting that natural killer cells, deficient in bg/bg mice, played no major role in determining adenoma susceptibility in this strain. No correlation was found between the susceptibility of various sublines to urethan-induced lung adenoma and the reported relative tumoricidal capacities of the peritoneal macrophages from these sublines.