INDUCTION OF MAMMARY-CANCER AND LYMPHOMA BY MULTIPLE, LOW ORAL DOSES OF 7,12-DIMETHYLBENZ[A]ANTHRACENE IN SENCAR MICE

Existing models of mouse mammary carcinogenesis induced by the model p olycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) t ypically use a small number of bolus doses applied intragastrically, I n contrast to this, typical human exposures to carcinogens are thought to be at lower doses and to occur with chronic or sporadic timing, Wh en the classical dosage (1 mg DMBA given once a week for 6 weeks) was split into five daily doses of 200 mu g given intragastrically to fema le SENCAR mice each week for 6 weeks, toxicity was high and the major tumor type seen was lymphoma, Lowering the dose to 60 mu g/day gave le ss toxicity, a 75% incidence of lymphoma and a 30% incidence of mammar y carcinoma, However, 20 mu g DMBA given five times per week for 6 wee ks resulted in a 65-70% incidence of mammary carcinoma within similar to 50 weeks, This represents a 50-fold lower daily dosage of DMBA than that used in the classical model, DNA was prepared from 10 mammary ad enocarcinomas and 10 lymphomas and exons 1 and 2 of the H-ras1, K-ras and N-ras genes were sequenced using PCR techniques, Mutations alterin g codons 12 or 61 of one of the ras family genes were found in 4/10 ma mmary carcinomas and 5/10 lymphomas, Three mammary tumors exhibited co don 61 mutations, one in each of the genes studied, and a fourth tumor contained a codon 12 mutation in the K-ras gene, Among the lymphomas, two mutations in codon 12 of K-ras, one mutation in codon 61 of K-ras and two mutations in codon 61 of N-ras were also found, Each of the m utations could be interpreted as a G-->T or A-->T transversion, It is suggested that the high incidence of lymphoma at the higher, repetitiv e doses may be related to immunotoxicity. These low dose models of lym phomagenesis and mammary carcinogenesis should prove useful for tests of chemopreventive agents that target the initiation phase of carcinog enesis.