Cisplatin.

Abstract

Cisplatin is a widely used anti-cancer drug that is exceptionally effective against testicular cancer. trans-DDP, the geometric isomer of cisplatin, is ineffective as a chemotherapeutic agent. The anti-tumour activity of cisplatin is generally attributed to its formation of DNA adducts, both intrastrand and interstrand crosslinks, which induce structural distortions in DNA. The DNA adducts of cisplatin are thought to mediate its cytotoxic effects by inhibiting DNA replication and transcription and, ultimately, by inducing programmed cell death, or apoptosis. The adducts of both cis- and trans-DDP are removed from DNA by the nucleotide-excision-repair pathway. Cellular proteins possessing certain DNA-binding motifs, including the HMG domain, bind selectively to DNA modified by cisplatin, but not to DNA adducts of trans-DDP; evidence suggests a possible role for these proteins in modulating cisplatin cytotoxicity. Both intrinsic and drug-induced resistance often limit the success of cisplatin; several specific mechanisms of cisplatin resistance have been identified.