Mutation Spectra in Cisplatin- and Transplatin-treated GDL1 Cells Clarified the Different Mode of Action of These Compounds in Mammalian Cells

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  • Takeiri Akira
    Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
  • Mishima Masayuki
    Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
  • Tanaka Kenji
    Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
  • Shioda Akifumi
    Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
  • Harada Asako
    Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
  • Masumura Ken-ichi
    Division of Genetics and Mutagenesis, National Institute of Health Sciences
  • Nohmi Takehiko
    Division of Genetics and Mutagenesis, National Institute of Health Sciences

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Cisplatin is an active antitumor drug but its stereoisomer, i.e., transplatin, is clinically inactive. We characterized the gene mutations induced by both isomers using cell line GDL1 established from gpt delta transgenic mice. Because cisplatin exhibited about 100 times higher cytotoxicity than transplatin, the cells were treated with cisplatin at doses of 0.25, 0.5, and 1 μg/mL and with transplatin at doses of 12.5, 25, and 50 μg/mL for 24 h. After an additional 2- to 8-day culture, mutant frequencies (MFs) with both Spi- and 6-thioguanine (6-TG) selection were determined. In Spi- selection, MFs in cisplatin- or transplatin-treated cells showed an increase of up to twofold that of vehicle-treated cells. A midsize deletion less than 1 kilo base pair (kbp) in size and single base deletions in non-run sequences were significantly induced by treatment with both compounds. In 6-TG selection, MFs increased up to 3.7-fold in the cisplatin-treated cells and 2.6-fold in transplatin-treated cells compared to vehicle-treated cells. Hotspots of cisplatin- and transplatin-induced mutations were found in 5′-NGG-3′, 5′-GGN-3′, and 5′-GNG-3′ sequences (N is the mutated nucleotide) and 5′-GCG-3′, 5′-GCCG-3′, 5′-GCN-3′, and 5′-GGGN-3′ (G, C, or N is the mutated nucleotide), respectively. These findings are consistent with previous reports using cell-free systems that cisplatin induces intrastrand crosslinks between two purine bases in 5′-GG-3′, 5′-AG-3′, and 5′-GNG-3′ and that transplatin primarily forms mono adducts in the guanine bases and needs multiple guanine adducts to form crosslinks. We suggest that intrastrand crosslinks play key roles in the cytotoxicity and mutagenicity induced by these two platinum compounds and that the more efficient formation of intrastrand crosslinks of cisplatin compared to transplatin may account for the potent cytotoxicity and clinical activity. The spectral analysis of mutations using GDL1 cells would provide valuable information on the mechanisms underlying the mutagenesis induced by the platinum stereoisomers.<br>

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