Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells
Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells
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DOI：
10.1002/ijc.20216
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发表时间：
2004-07-20
影响因子：
6.4
通讯作者：
Tanabe, S
中科院分区：
文献类型：
--
作者：
Yoshikawa, M;Ikegami, Y;Tanabe, S
伊立替康(7-ethyl-10 - [4 - (1-piperidino) 1-piperidino] -carbonyloxycamptothecin;CPT-11)是一种广泛使用的有效抗肿瘤药物，可抑制哺乳动物DNA拓扑异构酶I (Topo I)；然而，ABCG2 （BCRP/MXR/ABCP）的过表达可以使癌细胞对CPT-11的活性形式SN-38产生耐药性。我们最近证明，从abcg2过表达PC-6/SN2-5H细胞制备的质膜囊泡以atp依赖的方式运输SN-38及其葡萄糖醛酸盐偶联物（Nakatomi等人，Biochem Biophys Res commin 2001;288:827-32）。在本研究中，我们共鉴定了14种新的喜树碱（CPT），它们对Topo I的抑制和对ABCG2的底物特异性都有类似作用。所有被测试的CPT类似物，在位置10和11上有不同的取代，在无细胞系统中强烈抑制Topo I的活性，SN-38也是如此。然而，它们在耐sn -38的PC-6/SN2-5H2细胞系中的抗肿瘤活性变化很大，与细胞内积累水平相关。我们利用PC-6/SN2-5H2细胞和abcg2转染的HEK-293细胞制备的质膜囊泡，检测了这些CPT类似物的atp依赖性转运。基于ABCG2的底物特异性。因此，我们强烈建议具有高极性的CPT类似物是ABCG2的良好底物，因此可以有效地从癌细胞中挤出。在这种情况下，为了避免abcg2相关的耐药，低极性CPT类似物被认为是有效的先导化合物。本研究为发现新的基于cpt的耐药人类癌症化疗药物提供了一条实用的途径。(C) 2004 Wiley-Liss, Inc。
Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I); however, overexpression of ABCG2 (BCRP/MXR/ABCP) can confer cancer cell resistance to SN-38, the active form of CPT-11. We have recently demonstrated that plasma membrane vesicles prepared from ABCG2-overexpressing PC-6/SN2-5H cells transported SN-38 and its glucuronide conjugate in an ATP-dependent manner (Nakatomi et al., Biochem Biophys Res Commun 2001;288:827-32). In the present study, we have characterized a total of 14 new camptothecin (CPT), analogues with respect to both the inhibition of Topo I and the substrate specificity of ABCG2. All of the tested CPT analogues, which have different substitutions at positions 10 and 11, strongly inhibited the Topo I activity in a cell-free system, as did SN-38. Their antitumor activities in the SN-38-resistant PC-6/SN2-5H2 cell line greatly varied, however, being correlated with intracellular accumulation levels. We have examined ATP-dependent transport of those CPT analogues by using plasma membrane vesicles prepared from both PC-6/SN2-5H2 cells and ABCG2-transfected HEK-293 cells. Based on the substrate specificity of ABCG2. thus evaluated, it is strongly suggested that CPT analogues with high polarity are good substrates for ABCG2 and are therefore effectively extruded from cancer cells. In this context, to circumvent ABCG2-associated drug resistance, low-polarity CPT analogues are considered to be potent lead compounds. The present study provides a practical approach to discover new CPT-based drugs for the chemotherapy of drug-resistant human cancer. (C) 2004 Wiley-Liss, Inc.