In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer.
In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer.
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DOI：
10.1038/sj.bjc.6600290
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发表时间：
2002-05-20
影响因子：
8.8
通讯作者：
Jodrell, D I
中科院分区：
文献类型：
--
作者：
Aird, R E;Cummings, J;Ritchie, A A;Muir, M;Morris, R E;Chen, H;Sadler, P J;Jodrell, D I
与含铂化合物相比，钌络合物提供了降低毒性的潜力、新的作用机制、非交叉抗性和不同的活性谱。13个新的钌（II）有机金属芳烃配合物已被评估的活性（在体外和体内）在人类卵巢癌的模型，并建立在顺铂和多药耐药变异的交叉耐药谱。在A2780亲本细胞中，两种化合物（RM 175和HC 29）与卡铂（6 μM）等效，最具活性的化合物（HC 11）与顺铂（0.6 μ M）等效，获得了广泛的IC 50值（0.5至>100 μM）。稳定的双齿螯合配体（乙二胺），更疏水的芳烃配体（四氢蒽）和一个单一的配体交换中心（氯化物）与活性增加。六种活性钌（II）化合物在A2780 cis细胞系中均无交叉耐药，证明其对顺铂/卡铂的耐药性为10倍，其机制至少部分涉及通过甲基化沉默MLH 1蛋白表达。在P-170糖蛋白过表达的多药耐药细胞系2780 AD中观察到不同程度的交叉耐药，其可通过与维拉帕米共同治疗逆转。RM 175在A2780异种移植物中的体内活性以及A2780 cis异种移植物中的非交叉抗性和2780 AD异种移植物中的活性缺乏被确立。在顺铂耐药模型中的高活性与非交叉耐药性相结合，值得进一步开发这组新的抗癌化合物。英国癌症杂志（2002）86，1652-1657。DOI：10.1038/sj/bjc/6600290 www.bjcancer.com © 2002英国癌症研究中心
Ruthenium complexes offer the potential of reduced toxicity, a novel mechanism of action, non-cross resistance and a different spectrum of activity compared to platinum containing compounds. Thirteen novel ruthenium(II) organometallic arene complexes have been evaluated for activity (in vitro and in vivo) in models of human ovarian cancer, and cross-resistance profiles established in cisplatin and multi-drug-resistant variants. A broad range of IC50 values was obtained (0.5 to >100 μM) in A2780 parental cells with two compounds (RM175 and HC29) equipotent to carboplatin (6 μM), and the most active compound (HC11) equipotent to cisplatin (0.6 μM). Stable bi-dentate chelating ligands (ethylenediamine), a more hydrophobic arene ligand (tetrahydroanthracene) and a single ligand exchange centre (chloride) were associated with increased activity. None of the six active ruthenium(II) compounds were cross-resistant in the A2780cis cell line, demonstrated to be 10-fold resistant to cisplatin/carboplatin by a mechanism involving, at least in part, silencing of MLH1 protein expression via methylation. Varying degrees of cross-resistance were observed in the P-170 glycoprotein overexpressing multi-drug-resistant cell line 2780AD that could be reversed by co-treatment with verapamil. In vivo activity was established with RM175 in the A2780 xenograft together with non-cross-resistance in the A2780cis xenograft and a lack of activity in the 2780AD xenograft. High activity coupled to non cross-resistance in cisplatin resistant models merit further development of this novel group of anticancer compounds. British Journal of Cancer (2002) 86, 1652–1657. DOI: 10.1038/sj/bjc/6600290 www.bjcancer.com © 2002 Cancer Research UK