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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
German Cancer Research Center, Institute of Biochemistry D-6900 Heidelberg
1Nuclear Research Center, Department of Genetics and Toxicology D-7500 Karlsruhe, FRG
Using the multistage (initiation-conversion-promotion) protocol we have studied the effects of methyl methane-sulfonate (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 µmol 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 µmol MMS was found to be almost as clastogenic as 10 µmol of the convertogenic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), whereas the non-convertogenic promoter 12-O-retinoylphorbol-13-acetate (TPA, 10 nmol) did not induce chromosomal aberrations in viva. In combination with initiation by 7,12-dimethylbenz[a]anthracene (DMBA) and promotion by RPA, MMS (2 x 100 µmol) 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.
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