Inhibition of carcinogen-induced chromosomal aberrations by an anticarcinogenic protease inhibitor.

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Abstract
Chemical- and radiation-induced carcinogenesis might require at least the following 2 specific chromosomal events that must coincide within a single target cell: induction of chromosomal changes, possibly mutations, that are recessive and therefore latent in diploid somatic cells; aberrant mitotic segregation events that will convert the heterozygous cell, created by the 1st process, into a homozygous or hemizygous cell through chromosomal rearrangements. The prediction that an inhibitor of induced carcinogenesis may inhibit 1 or both of these chromosomal events was tested by studying the effects of antipain, a protease inhibitor and known inhibitor of carcinogenesis, on N-methyl-N''-nitro-N-nitrosoguanidine (MNNG)-induced mutagenesis, chromosomal aberrations, sister chromatid exchanges and cell killing in V79 Chinese hamster [lung fibroblast] cells. Antipain inhibited MNNG-induced chromosomal exchanges and all other chromosomal aberrations exclusively. MNNG-induced DNA lesions may cause chromosomal aberrations which arise through an antipain-sensitive cellular process. Probably, some chromosomal rearrangement is a rate-limiting step in carcinogenesis and mutagenesis alone, if required, is not sufficient to accomplish carcinogenesis.