Luo F R, Wyrick S D, Chaney S G
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599, USA.
Oncol Res. 1998;10(11-12):595-603.
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.
铂类抗癌药物的生物转化产物被认为与药物疗效和毒性有关。本研究旨在确定密切相关的1,2 - 二氨基环己烷 - 铂（dach - Pt）化合物奥沙利铂和奥马铂的疗效主要是由母体药物还是由其生物转化产物之一所决定。基于对人结肠癌细胞（HT - 29）的体外细胞毒性以及奥沙利铂体内给药后浓度的考虑，我们的数据表明，奥沙利铂的疗效主要由母体药物的血浆水平决定，生物转化产物Pt(dach)Cl2、Pt(dach)(H2O)Cl和Pt(dach)(H2O)2的贡献较小。含氨基酸的稳定生物转化产物没有任何显著的细胞毒性。相比之下，我们的数据表明，奥马铂的疗效主要由Pt(dach)Cl2的血浆水平决定。奥沙利铂、Pt(dach)Cl2和Pt(dach)(H2O)Cl的细胞毒性与其细胞摄取量大致成正比，而奥马铂、Pt(dach)(H2O)2和Pt(dach)(Met)的细胞毒性低于根据其摄取量所预测的值。用等摩尔外部浓度的Pt(dach)Cl2和奥沙利铂处理HT - 29细胞后，Pt(dach)Cl2处理组形成的Pt - DNA加合物比奥沙利铂处理组多两倍。然而，Pt(dach)Cl2处理组细胞内的Pt(dach)Cl2水平比奥沙利铂处理组高30倍。这些数据表明，奥沙利铂在细胞内转化为Pt(dach)Cl2对Pt - DNA加合物形成及奥沙利铂由此产生的细胞毒性的贡献较小。
