Inhibition of carcinogen-induced chromosomal aberrations by an anticarcinogenic protease inhibitor.
It was hypothesized that chemicals- and radiation-induced carcinogenesis might require at least two specific chromosomal events that must coincide within a single target cell: (i) induction of chromosomal changes, possibly mutations, that are recessive and therefore latent in diploid somatic cells and (ii) aberrant mitotic segregation events that will convert the heterozygous cell, created by the first process, into a homozygous or hemizygous cell through chromosomal rearrangements. Hence, we tested the prediction that an inhibitor of induced carcinogenesis may inhibit one or both of these chromosomal events 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 cells. We show that antipain inhibited MNNG-induced chromosomal exchanges and all other chromosomal aberrations exclusively. This results leads us to postulate that MNNG-induced DNA lesions cause chromosomal aberrations which arise through an antipain-sensitive cellular process, that some chromosomal rearrangement is a rate-limiting step in carcinogenesis, and that mutagenesis alone, if required, is not sufficient to accomplish carcinogenesis.
D000818:Animals; D000976:Antipain / Q000494:pharmacology; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002869:Chromosome Aberrations / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D007976:Leupeptins / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009154:Mutation; D011480:Protease Inhibitors / Q000494:pharmacology*; D012854:Sister Chromatid Exchange; D013997:Time Factors
D002273:Carcinogens; D007976:Leupeptins; D011480:Protease Inhibitors; D008769:Methylnitronitrosoguanidine; D000976:Antipain