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-diaminocyclohe xane-Pt (dach-Pt) compounds oxaliplatin and ormaplatin were determined prim arily by the parent drugs or by one of their biotransformation products. Ba sed on consideration of both in vitro cytotoxicity in human colon carcinoma cells (HT-29) and concentrations following oxaliplatin administration in v ivo, our data suggest that the efficacy of oxaliplatin is primarily determi ned by the plasma levels of the parent drug, with the biotransformation pro ducts Pt(dach)Cl-2, Pt(dach)(H2O)Cl, and Pt(dach)(H2O)(2) making only minor contributions. The stable biotransformation products containing amino acid s 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)Cl-2. The cytotoxicity of oxaliplatin, Pt(dach)Cl-2, 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 t han predicted from their uptake. Treatment of HT-29 cells with equimolar ex ternal concentrations of Pt(dach)Cl-2 and oxaliplatin resulted in the forma tion of twofold more Pt-DNA adducts following Pt(dach)Cl-2 treatment than f ollowing oxaliplatin treatment. However, intracellular Pt(dach)Cl-2 levels were 30-fold higher for Pt(dach)Cl-2-treated cells than for oxaliplatin-tre ated cells. These data suggest that intracellular conversion of oxaliplatin to Pt(dach)Cl-2 makes only a minor contribution to Pt-DNA adduct formation and the resultant cytotoxicity of oxaliplatin.