Cellular and Molecular Life Sciences CMLS

, Volume 57, Issue 8, pp 1229–1235

Molecular mechanisms involved in cisplatin cytotoxicity

  • P. Jordan
  • M. Carmo-Fonseca*

DOI: 10.1007/PL00000762

Cite this article as:
Jordan, P. & Carmo-Fonseca*, M. CMLS, Cell. Mol. Life Sci. (2000) 57: 1229. doi:10.1007/PL00000762

Abstract.

cis-diamminedichloroplatinum(II) or cisplatin is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin cross-links to DNA, forming intra- and interstrand adducts, which bend and unwind the duplex and attract high-mobility-group domain and other proteins. Presumably due to a shielding effect caused by these proteins, the cisplatin-modified DNA is poorly repaired. The resulting DNA damage triggers cell-cycle arrest and apoptosis. Although it is still debatable whether the clinical success of cisplatin relies primarily on its ability to trigger apoptosis, at least two distinct pathways have been proposed to contribute to cisplatin-induced apoptosis in vitro. One involves the tumour-suppressor protein p53, the other is mediated 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 play a key role in the cytotoxicity of the drug, and loss of the mismatch repair activity is known to cause cisplatin resistance, a major problem in antineoplastic therapy. Clearly, a better understanding of the signalling networks involved in cisplatin toxicity should provide a rational basis for the development of new therapeutic strategies.

Key words. Cisplatin; anticancer drugs; DNA adducts; DNA repair; apoptosis; nucleolus. 

Copyright information

© Birkhäuser Verlag Basel, 2000

Authors and Affiliations

  • P. Jordan
    • 1
  • M. Carmo-Fonseca*
    • 2
  1. 1.Laboratório de Oncobiologia, Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa (Portugal)PT
  2. 2.Instituto de Histologia e Embriologia, Faculdade de Medicina, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal), Fax + 351 21 795 17 80, e-mail: carmo.fonseca@fm.ul.pt PT