Cytotoxicity, cellular uptake, and cellular biotransformations of oxaliplatin in human colon carcinoma cells.
Cytotoxicity, cellular uptake, and cellular biotransformations of oxaliplatin in human colon carcinoma cells.
复制标题
奥沙利铂在人结肠癌细胞中的细胞毒性、细胞摄取和细胞生物转化。
作者：
F. Luo;S. Wyrick;S. Chaney
铂类抗癌药物的生物转化产物已被认为是药物疗效和毒性的原因。本研究旨在确定密切相关的1，2-二氨基环己烷-Pt（dach-Pt）化合物奥沙利铂和奥马铂的疗效是否主要由母体药物或其生物转化产物之一决定。基于对人结肠癌细胞（HT-29）体外细胞毒性和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取决于母体药物的血浆水平，生物转化产物Pt（dach）Cl 2、Pt（dach）（H2O）Cl和Pt（dach）（H2O）2仅起次要作用。含有氨基酸的稳定生物转化产物没有任何明显的细胞毒性。相反，我们的数据表明，奥马铂的疗效主要取决于Pt（dach）Cl 2的血浆水平。奥沙利铂、Pt（dach）Cl 2和Pt（dach）（H2O）Cl的细胞毒性与其细胞摄取大致成比例，而奥马铂、Pt（dach）（H2O）2和Pt（dach）（Met）的细胞毒性低于其摄取的预测值。用等摩尔外部浓度的Pt（dach）Cl 2和奥沙利铂处理HT-29细胞导致Pt（dach）Cl 2处理后形成的Pt-DNA加合物比奥沙利铂处理后多两倍。然而，Pt（dach）Cl 2处理的细胞的细胞内Pt（dach）Cl 2水平比奥沙利铂处理的细胞高30倍。这些数据表明，奥沙利铂在细胞内转化为Pt（dach）Cl 2对Pt-DNA加合物形成和奥沙利铂的细胞毒性仅产生微小影响。
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.