Tumor induction in initiated mouse skin by phorbol esters and methyl methanesulfonate: correlation between chromosomal damage and conversion ('stage I of tumor promotion') in vivo.

Using the multistage (initiation-conversion-promotion) protocol we have studied the effects of methyl methanesulfonate (MMS), a well-known alkylating and clastogenic agent, on tumor development in NMRI mouse skin in vivo. When topically applied in a dose up to 400 mumol MMS did not exhibit any initiating efficacy while under identical conditions chromosomal damage (mainly breaks and gaps) was induced in epidermis. A dose of 100 mumol MMS was found to be almost as clastogenic as 10 nmol of the convertogenic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), whereas the non-convertogenic promoter 12-O-retinoylphorbol-13-acetate (RPA, 10 nmol) did not induce chromosomal aberrations in vivo. In combination with initiation by 7,12-dimethylbenz[a]anthracene (DMBA) and promotion by RPA, MMS (2 x 100 mumol) turned out to be a rather powerful convertogenic agent ('stage I tumor promoter'). This tumor-inducing efficacy of MMS was synergistically increased by simultaneous application of RPA. These results support the concept that the induction of chromosomal aberrations plays an important role in skin tumor development, i.e. in the conversion stage.