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.