Transplacental mutagenicity of cisplatin: H-ras codon 12 and 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 transplacentally. For characterization of the transplacental mutagenicity of cisplatin, tumors initiated in fetal skin by cisplatin or 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by postnatal 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were analyzed for H-ras mutations by 'cold' single-strand conformation polymorphism analysis and direct sequencing. The expected high incidence of exon II codon 61 mutations (20/20) was found in transplacental DMBA-initiated tumors, with no exon I change. By contrast, 6/10 cisplatin tumors had seven mutations in codons 12 or 13 of exon I, all at GpG dinucleotides. Four of these were unique codon 13 GGC --> GTC changes, significantly different from the DMBA group and from historical TPA-only controls. The activation of codons 12 and 13 by cisplatin is in accord with the known in vitro preference of cisplatin for GpG sites for intrastrand cross-linking adduct formation. These results provide the first evidence that cisplatin can act transplacentally to cause specific mutations in fetal skin that are not seen in skin tumors caused by treatment of adult skin with this agent. This is evidence for unique molecular fetal carcinogenic pathways and underscores concern about human fetal risk due to maternal cisplatin treatment.
Munoz
E F
EF
Intramural Research Support Program, SAIC Frederick, National Cancer Institute--Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Diwan
B A
BA
Calvert
R J
RJ
Weghorst
C M
CM
Anderson
J
J
Rice
J M
JM
Buzard
G S
GS
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D003062:Codon; D005260:Female; D005333:Fetus / Q000187:drug effects*; D011905:Genes, ras; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D011247:Pregnancy; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics*
D000970:Antineoplastic Agents; D003062:Codon; D009153:Mutagens; D015127:9,10-Dimethyl-1,2-benzanthracene; D002945:Cisplatin