The role of DNA mismatch repair in cisplatin mutagenicity

Cisplatin (DDP) is used with varying success for the treatment of a wide spectrum of human cancers. The most abundant lesions produced in DNA are intrastrand crosslinks, which are believed to account for not only the cytotoxic action but also the mutagenicity of the drug. The molecular basis for the mutagenicity of DDP adducts is believed to be related to bypass replication across the adducts by DNA polymerase. This results in misincorporation of non-complimentary bases by polymerase beta which, if left unpaired, will generate point or frameshift mutations. An important replication-associated correction function is provided by the post-replicative DNA mismatch repair (MMR) system. Loss of MMR activity is well documented to result in increased mutation rates and instability of genomic DNA. Inactivation of the MMR system also augments the intrinsic mutagenicity of DDP and enhances the risk of developing cells resistant to other drugs commonly used in combination with DDP. A future challenge will be to assess the clinical significance of the presence of MMR-deficient cells in tumors, and investigate new approaches to circumvent such multidrug resistance.