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 1 0 consecutive generations of bidirectional selective breeding present a very large difference in responsiveness to two-stage skin carcinogen esis. Car-S mice initiated with 0.5 mu g 9,10-dimethyl-1,2-benzanthrac ene (DMBA) and promoted with 0.25 mu g 12-O-tetradecanoylphorbol-13-ac etate (TPA) for 77 days showed a papilloma incidence of 88% and a tumo ur 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 compa rable papilloma response: incidence 65%, tumour multiplicity 3.2 +/- 0 .6 and tumour induction rate 0.288. The difference in papilloma respon se between the two lines is due to the interaction of genetic and envi ronmental factors. In order to overcome the genetic effect with enviro nmental 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, tha t of TPA 40 times and the promotion time augmented by 44%. Papilloma t o carcinoma conversion 112 days after the end of promotion depends on the DMBA and TPA doses applied. The number of carcinomas induced in Ca r-S mice and in (Car-SXCarR) F1 hybrids was larger than that induced i n Car-R mice, but the ratio of carcinoma conversion was lower, therefo re a larger proportion of the small number of papillomas induced in th e Car-R mice progressed to malignancy. The dominance effect measured i n (Car-SxCar-R) F1 hybrids demonstrated that the susceptibility to pap illoma induction was an incomplete dominant character (d/a = 0.38), wh ereas for carcinoma conversion the resistance was incompletely dominan t (d/a = -0.49).