Biochemical mechanisms of cisplatin cytotoxicity.
Since the discovery by Rosenberg and collaborators of the antitumor activity of cisplatin 35 years ago, three platinum antitumor drugs (cisplatin, carboplatin and oxaliplatin) have enjoyed a huge clinical and commercial hit. Ever since the initial discovery of the anticancer activity of cisplatin, major efforts have been devoted to elucidate the biochemical mechanisms of antitumor activity of cisplatin in order to be able to rationally design novel platinum based drugs with superior pharmacological profiles. In this report we attempt to provide a current picture of the known facts pertaining to the mechanism of action of the drug, including those involved in drug uptake, DNA damage signals transduction, and cell death through apoptosis or necrosis. A deep knowledge of the biochemical mechanisms, which are triggered in the tumor cell in response to cisplatin injury not only may lead to the design of more efficient platinum antitumor drugs but also may provide new therapeutic strategies based on the biochemical modulation of cisplatin activity.
Cepeda
Victoria
V
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Facultad de Ciencias, Universidad Autónoma de Madrid, 28049-Madrid, Spain.
Fuertes
Miguel A
MA
Castilla
Josefina
J
Alonso
Carlos
C
Quevedo
Celia
C
Pérez
Jose M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D002945:Cisplatin