TRANSPLACENTAL MUTAGENICITY OF CISPLATIN - H-RAS CODON-12 AND CODON-13 MUTATIONS IN SKIN TUMORS OF SENCAR MICE

Cisplatin is an anticancer agent sometimes used in pregnant women, It is also a potent initiator of skin tumors in mice when administered tr ansplacentally, For characterization of the transplacental mutagenicit y of cisplatin, tumors initiated in fetal skin by cisplatin or 7,12-di methylbenz-[n]anthracene (DMBA) and promoted by postnatal 12-O-tetrade canoyl-phorbol-13-acetate (TPA) were analyzed for H-ms mutations by 'c old' single-strand conformation polymorphism analysis and direct seque ncing, The expected high incidence of exon II codon 61 mutations (20/2 0) was found in transplacental DMBA-initiated tumors, with no exon I c hange, By contrast, 6/10 cisplatin tumors had seven mutations in codon s 12 or 13 of exon I, all at GpG dinucleotides, Four of these were uni que codon 13 GGC --> GTC changes, significantly different from the DMB A group and from historical TPA-only controls, The activation of codon s 12 and 13 by cisplatin is in accord with the known in vitro preferen ce of cisplatin for GpG sites for intrastrand cross-linking adduct for mation, These results provide the first evidence that cisplatin can ac t transplacentally to cause specific mutations in fetal skin that are not seen in skin tumors caused by treatment of adult skin with this ag ent, This is evidence for unique molecular fetal carcinogenic pathways and underscores concern about human fetal risk due to maternal cispla tin treatment.