Zhang Shuzhong, Lovejoy Katherine S, Shima James E, Lagpacan Leah L, Shu Yan, Lapuk Anna, Chen Ying, Komori Takafumi, Gray Joe W, Chen Xin, Lippard Stephen J, Giacomini Kathleen M
Department of Biopharmaceutical Sciences, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94158, USA.
Cancer Res. 2006 Sep 1;66(17):8847-57. doi: 10.1158/0008-5472.CAN-06-0769.
Although the platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have similar DNA-binding properties, only oxaliplatin is active against colorectal tumors. The mechanisms for this tumor specificity of platinum-based compounds are poorly understood but could be related to differences in uptake. This study shows that the human organic cation transporters (OCT) 1 and 2 (SLC22A1 and SLC22A2) markedly increase oxaliplatin, but not cisplatin or carboplatin, accumulation and cytotoxicity in transfected cells, indicating that oxaliplatin is an excellent substrate of these transporters. The cytotoxicity of oxaliplatin was greater than that of cisplatin in six colon cancer cell lines [mean +/- SE of IC(50) in the six cell lines, 3.9 +/- 1.4 micromol/L (oxaliplatin) versus 11 +/- 2.0 micromol/L (cisplatin)] but was reduced by an OCT inhibitor, cimetidine, to a level similar to, or even lower than that of, cisplatin (29 +/- 11 micromol/L for oxaliplatin versus 19 +/- 4.3 micromol/L for cisplatin). Structure-activity studies indicated that organic functionalities on nonleaving groups coordinated to platinum are critical for selective uptake by OCTs. These results indicate that OCT1 and OCT2 are major determinants of the anticancer activity of oxaliplatin and may contribute to its antitumor specificity. They also strongly suggest that expression of OCTs in tumors should be investigated as markers for selecting specific platinum-based therapies in individual patients. The development of new anticancer drugs, specifically targeted to OCTs, represents a novel strategy for targeted drug therapy. The results of the present structure-activity studies indicate specific tactics for realizing this goal.
尽管铂类抗癌药物顺铂、卡铂和奥沙利铂具有相似的DNA结合特性，但只有奥沙利铂对结直肠癌具有活性。铂类化合物这种肿瘤特异性的机制尚不清楚，但可能与摄取差异有关。本研究表明，人类有机阳离子转运体（OCT）1和2（SLC22A1和SLC22A2）显著增加奥沙利铂（而非顺铂或卡铂）在转染细胞中的蓄积和细胞毒性，表明奥沙利铂是这些转运体的优良底物。在六种结肠癌细胞系中，奥沙利铂的细胞毒性大于顺铂[六种细胞系中IC(50)的平均值±标准误，奥沙利铂为3.9±1.4 μmol/L，顺铂为11±2.0 μmol/L]，但被OCT抑制剂西咪替丁降低至与顺铂相似甚至更低的水平（奥沙利铂为29±11 μmol/L，顺铂为19±4.3 μmol/L）。构效关系研究表明，与铂配位的非离去基团上的有机官能团对于OCT的选择性摄取至关重要。这些结果表明，OCT1和OCT2是奥沙利铂抗癌活性的主要决定因素，可能有助于其抗肿瘤特异性。它们还强烈提示，应研究肿瘤中OCT的表达情况，作为为个体患者选择特定铂类疗法的标志物。开发专门靶向OCT的新型抗癌药物代表了一种靶向药物治疗的新策略。本构效关系研究的结果表明了实现这一目标的具体策略。
