Molecular mechanisms involved in cisplatin cytotoxicity

Citation
P. Jordan et M. Carmo-fonseca, Molecular mechanisms involved in cisplatin cytotoxicity, CELL MOL L, 57(8-9), 2000, pp. 1229-1235
Citations number
84
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Cell & Developmental Biology
Journal title
CELLULAR AND MOLECULAR LIFE SCIENCES
ISSN journal
1420-682X → ACNP
Volume
57
Issue
8-9
Year of publication
2000
Pages
1229 - 1235
Database
ISI
SICI code
1420-682X(200008)57:8-9<1229:MMIICC>2.0.ZU;2-8
Abstract
cis-diamminedichloroplatinum(II) or cisplatin is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin cross-links to DNA, formin g intra- and interstrand adducts, which bend and unwind the duplex and attr act high-mobility-group domain and other proteins. Presumably due to a shie lding effect caused by these proteins, the cisplatin-modified DNA is poorly repaired. The resulting DNA damage triggers cell-cycle arrest and apoptosi s. Although it is still debatable whether the clinical success of cisplatin relies primarily on its ability to trigger apoptosis, at least two distinc t pathways have been proposed to contribute to cisplatin-induced apoptosis in vitro. One involves the tumour-suppressor protein p53, the other is medi ated by the p53-related protein p73. Coupling cisplatin damage to apoptosis requires mismatch repair activity, and recent observations further suggest involvement of the homologous recombinatorial repair system. At present it is generally accepted that abortive attempts to repair the DNA lesions pla y a key role in the cytotoxicity of the drug, and loss of the mismatch repa ir activity is known to cause cisplatin resistance, a major problem in anti neoplastic therapy. Clearly, a better understanding of the signalling netwo rks involved in cisplatin toxicity should provide a rational basis for the development of new therapeutic strategies.