Organic cation transporters are determinants of oxaliplatin cytotoxicity
Organic cation transporters are determinants of oxaliplatin cytotoxicity
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DOI：
10.1158/0008-5472.can-06-0769
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Giacomini, Kathleen M.
中科院分区：
文献类型：
--
作者：
Zhang, Shuzhong;Lovejoy, Katherine S.;Giacomini, Kathleen M.
虽然铂类抗癌药物顺铂、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肿瘤有活性。铂类化合物的这种肿瘤特异性的机制知之甚少，但可能与摄取的差异有关。本研究表明，人有机阳离子转运蛋白（OCT）1和2（SLC 22 A1和SLC 22 A2）可显著增加转染细胞中奥沙利铂的蓄积和细胞毒性，但不增加顺铂或卡铂的蓄积和细胞毒性，表明奥沙利铂是这些转运蛋白的优良底物。在6种结肠癌细胞系中，奥沙利铂的细胞毒性大于顺铂[6种细胞系中IC 50的平均值+/- SE为3.9 +/- 1.4 μ mol/l，（奥沙利铂）vs 11 +/- 2.0 μ mol/L（顺铂）]，但被OCT抑制剂西咪替丁降低至类似于或甚至低于顺铂的水平，顺铂（奥沙利铂29 +/- 11 μ mol/L vs顺铂19 +/- 4.3 μ mol/L）。结构-活性研究表明，非离去基团上的有机官能团与铂配位对于OCT的选择性摄取至关重要。这些结果表明，OCT 1和OCT 2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。他们还强烈建议，应研究肿瘤中OCT的表达，作为在个体患者中选择特定铂类药物治疗的标志物。新的抗癌药物，特别是针对OCT的开发，代表了靶向药物治疗的新策略。目前的结构-活性研究的结果表明，实现这一目标的具体策略。
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 IC50 in the six cell lines, 3.9 +/- 1.4 mu mol/l, (oxaliplatin) versus 11 +/- 2.0 mu mol/L (cisplatin)] but was reduced by an OCT inhibitor, cimetidine, to a level similar to, or even lower than that of, cisplatin (29 +/- 11 mu mol/L for oxaliplatin versus 19 +/- 4.3 mu mol/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.