Influence of sex and carcinogen treatment protocol on tumor latency and frequency of K-ras mutations in N-methyl-N-nitrosourea-induced lymphomas.

N-methyl-N-nitrosourea (MNU) induces thymic lymphomas in AKR mice after a 2-3 month latency. This study shows that hormonal factors profoundly influence MNU-induced lymphomagenesis. Tumor development is accelerated in females compared to males, regardless of whether a single high dose or multiple low doses of MNU are administered. Testosterone is implicated in this phenomenon, since castrated mice develop MNU-induced lymphomas with the same latency as intact females, while ovariectomized females have the same pattern of tumor development as intact females. Furthermore, reconstitution experiments demonstrated that testosterone replacement suppresses MNU-induced lymphoma development in castrated males. Although tumor development is delayed in male compared to female mice, sex does not influence tumor immunophenotype, clonality or the frequency of ras mutations in animals given identical MNU treatment protocols. In contrast, the frequency of ras mutations is dramatically altered depending on whether the animals are treated with a single high dose or multiple low doses of MNU. Nevertheless, there is no correlation between the presence of an activated K-ras allele and tumor latency. These data demonstrate that sex has a more profound influence on the progression of MNU-induced lymphomas than does the presence of an activated K-ras allele.