Molecular aspects of resistance to antitumor platinum drugs.
The processes by which cells develop resistance to antitumor platinum drugs have been the subject of intense research because resistance is a major obstacle for the clinical use of this class of drugs. It is therefore of great interest to understand the molecular and biochemical mechanisms that underlie resistance to platinum drugs and their biological effects. There is a large body of experimental evidence suggesting that the antitumor activity of platinum complexes stems from their ability to form on DNA various types of covalent adducts. As a result, research on DNA modifications by these drugs and their cellular processing has predominated. The resistance of tumor cells to platinum drugs has been attributed to several processes and an increased repair of platinum-DNA adducts is considered a most significant event. The present review summarizes recent insights into the effects of sulfur-containing compounds on DNA modifications by antitumor platinum complexes and how these modifications are repaired including how this repair is associated with their recognition by cellular, damaged-DNA binding-proteins. It strongly supports the view that changes in the structure of platinum drugs, resulting in DNA binding mode fundamentally different from that of "classical" cisplatin, will alter resistance pathways of platinum drugs, and may also modulate their pharmacological properties.
Brabec
Viktor
V
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, Brno, Czech Republic. brabec@ibp.cz
Kasparkova
Jana
J
D002945:Cisplatin / Q000627:therapeutic use*; D018736:DNA Adducts / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008967:Molecular Biology / Q000379:methods; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin
D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C114062:BBR 3464; D002945:Cisplatin