拓扑替康
喜树碱
拓扑异构酶
卵巢癌
米托蒽醌
序号38
Abcg2型
药理学
癌症研究
生物
化学
医学
伊立替康
癌症
生物化学
内科学
化疗
酶
基因
ATP结合盒运输机
结直肠癌
运输机
作者
Annemarie H. Van Hattum,Hennie M.M. Schlüper,Frederick H. Hausheer,Herbert M. Pinedo,Epie Boven
摘要
Abstract The novel camptothecin derivative BNP1350 (7‐[2‐trimethylsilyl)ethyl]‐20( S )‐camptothecin), also known as Karenitecin, has been developed for superior oral bioavailability and increased lactone stability. In our study, we describe the antiproliferative effects of BNP1350, SN‐38 and topotecan in 4 human ovarian cancer cell lines. BNP1350 was found to be slightly more potent than SN‐38 ( p <0.01) and was considerably more potent than topotecan ( p <0.01). We extended these studies to well‐established human ovarian cancer xenografts in which we compared the growth inhibition induced by BNP1350 with that of topotecan given in equitoxic schedules. The growth inhibition in all 3 xenografts induced by BNP1350 was ≥75%, which was significantly better than that resulting from topotecan ( p <0.05). We then selected BNP1350‐resistant variants of the A2780 human ovarian cancer cell line, 2780K4 (resistance factor: 41) and 2780K32 (resistance factor: 90), to analyze possible resistance mechanisms. These variants exhibited cross‐resistance against all camptothecins tested. In comparison with 2780K4 cells, 2780K32 cells were relatively more resistant against SN‐38, topotecan, DX‐8951f and BNP1350. In addition, 2780K32 cells were highly cross‐resistant against mitoxantrone. In both 2780K4 and 2780K32, the amount of topoisomerase I was not changed but the catalytic activity was reduced. Furthermore, 2780K32 cells clearly overexpressed the breast cancer resistance protein (BCRP), as demonstrated for both the gene and the protein. In contrast to topotecan, BNP1350 proved not to be a good substrate for BCRP. Overall, we conclude that BNP1350 offers advantages over topotecan expressed by high efficacy in experimental human ovarian cancer and poor affinity for BCRP. © 2002 Wiley‐Liss, Inc.
科研通智能强力驱动
Strongly Powered by AbleSci AI