GENETICS OF CHEMICAL CARCINOGENESIS .2. PAPILLOMA INDUCTION AND MALIGNANT CONVERSION IN SUSCEPTIBLE (CAR-S) AND RESISTANT (CAR-R) LINES OF MICE PRODUCED BY BIDIRECTIONAL SELECTIVE BREEDING AND IN THEIR (CAR-S X CAR-R) F1 HYBRIDS

Susceptible (Car-S) and resistant (Car-R) lines of mice separated by 10 consecutive generations of bidirectional selective breeding present a very large difference in responsiveness to two-stage skin carcinogenesis. Car-S mice initiated with 0.5 mu g 9,10-dimethyl-1,2-benzanthracene (DMBA) and promoted with 0.25 mu g 12-O-tetradecanoylphorbol-13-acetate (TPA) for 77 days showed a papilloma incidence of 88% and a tumour multiplicity of 3.2 +/- 0.4 (mean +/- SE), with a tumour induction rate of 0.415. Car-R mice initiated with larger DMBA and TPA doses (50 mu g and 20 mu g respectively) and promoted for 111 days gave a comparable papilloma response: incidence 65%, tumour multiplicity 3.2 +/- 0.6 and tumour induction rate 0.288. The difference in papilloma response between the two lines is due to the interaction of genetic and environmental factors. In order to overcome the genetic effect with environmental factors and induce in Car-R a papilloma response comparable to that of Car-S, the DMBA dose had to be increased up to 100 times, that of TPA 40 times and the promotion time augmented by 44%. Papilloma to carcinoma conversion 112 days after the end of promotion depends on the DMBA and TPA doses applied. The number of carcinomas induced in Car-S mice and in (Car-SXCarR) F1 hybrids was larger than that induced in Car-R mice, but the ratio of carcinoma conversion was lower, therefore a larger proportion of the small number of papillomas induced in the Car-R mice progressed to malignancy. The dominance effect measured in (Car-SxCar-R) F1 hybrids demonstrated that the susceptibility to papilloma induction was an incomplete dominant character (d/a = 0.38), whereas for carcinoma conversion the resistance was incompletely dominant (d/a = -0.49).