Cytotoxicity, cellular uptake, and cellular biotransformations of oxaliplatin in human colon carcinoma cells.
Biotransformation products of platinum anticancer drugs have been suggested to be responsible for drug efficacy and toxicity. This study was designed to determine whether the efficacy of the closely related 1,2-diaminocyclohexane-Pt (dach-Pt) compounds oxaliplatin and ormaplatin were determined primarily by the parent drugs or by one of their biotransformation products. Based on consideration of both in vitro cytotoxicity in human colon carcinoma cells (HT-29) and concentrations following oxaliplatin administration in vivo, our data suggest that the efficacy of oxaliplatin is primarily determined by the plasma levels of the parent drug, with the biotransformation products Pt(dach)Cl2, Pt(dach)(H2O)Cl, and Pt(dach)(H2O)2 making only minor contributions. The stable biotransformation products containing amino acids did not have any significant cytotoxicity. In contrast, our data suggest that the efficacy of ormaplatin is primarily determined by plasma levels of Pt(dach)Cl2. The cytotoxicity of oxaliplatin, Pt(dach)Cl2, and Pt(dach)(H2O)Cl was approximately proportional to their cellular uptake, whereas the cytotoxicity of ormaplatin, Pt(dach)(H2O)2, and Pt(dach)(Met) was less than predicted from their uptake. Treatment of HT-29 cells with equimolar external concentrations of Pt(dach)Cl2 and oxaliplatin resulted in the formation of twofold more Pt-DNA adducts following Pt(dach)Cl2 treatment than following oxaliplatin treatment. However, intracellular Pt(dach)Cl2 levels were 30-fold higher for Pt(dach)Cl2-treated cells than for oxaliplatin-treated cells. These data suggest that intracellular conversion of oxaliplatin to Pt(dach)Cl2 makes only a minor contribution to Pt-DNA adduct formation and the resultant cytotoxicity of oxaliplatin.
Luo
F R
FR
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599, USA.
Wyrick
S D
SD
Chaney
S G
SG
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D002277:Carcinoma / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018736:DNA Adducts / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077150:Oxaliplatin; D010984:Platinum / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum