一种texaphyrin-奥沙利铂缀合物，可克服癌细胞中顺铂耐药性的药理学和分子机制。
A texaphyrin-oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells.
作者信息
Arambula Jonathan F, Sessler Jonathan L, Siddik Zahid H
机构信息
Department of Chemistry and Biochemistry, Texas Institute for Diagnostics and Drug Development, The University of Texas, 1 University Station-A5300, Austin, TX 78712-0165, USA. ; Tel: +1 512 471 5009 ; Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 353, Houston, TX 77030, USA. Fax: +1 713 792 1204; Tel: +1 713 792 7746.
出版信息
Medchemcomm. 2012;3(10):1275-1281. doi: 10.1039/C2MD20206A.
Abstract
A texaphyrin-oxaliplatin conjugate, oxaliTEX, was designed to test the concept that a platinum analog can overcome defects in drug accumulation and p53-dependent DNA damage response in a tumor model expressing multifactorial mechanisms of cisplatin resistance. Cytotoxic studies resulted in a resistance factor of only 1.2, which essentially indicated complete reversal of resistance in 2780CP cells expressing a factor of 22 with cisplatin. Unlike cisplatin, oxaliTEX accumulated and formed DNA adducts, stabilized and activated p53 at similar levels in both sensitive and resistant cells, and induced apoptosis in both models. The ability and importance of a designer drug, such as oxaliTEX, to overcome cisplatin resistance by targeting two dominant resistance mechanisms is discussed.
摘要
设计了一种texaphyrin-奥沙利铂共轭物oxaliTEX，以验证这样一个概念：在表达顺铂耐药多因素机制的肿瘤模型中，铂类似物可以克服药物蓄积缺陷和p53依赖性DNA损伤反应。细胞毒性研究得出的耐药因子仅为1.2，这基本上表明在对顺铂耐药因子为22的2780CP细胞中耐药性完全逆转。与顺铂不同，oxaliTEX在敏感细胞和耐药细胞中均能蓄积并形成DNA加合物，以相似水平稳定并激活p53，并在两种模型中诱导细胞凋亡。本文讨论了诸如oxaliTEX这类设计药物通过靶向两种主要耐药机制克服顺铂耐药的能力及重要性。
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