FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance.
FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance.
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DOI：
10.1186/s12943-015-0362-9
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发表时间：
2015-04-28
期刊：
影响因子：
37.3
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Westover D;Ling X;Lam H;Welch J;Jin C;Gongora C;Del Rio M;Wani M;Li F
伊立替康是一种喜树碱类似物，目前在临床实践中用于治疗晚期结直肠癌。然而，药物外排泵 ABCG2 介导的获得性耐药是一个公认的问题。我们报道了一种新型喜树碱类似物 FL118，其抗癌活性优于伊立替康。在这项研究中，我们试图在具有高 ABCG2 活性的人类癌症体外和体内模型中研究 FL118 相对于伊立替康或其活性代谢物 SN-38 的效力。我们还试图评估几种带有 B 环取代的 FL118 类似物的效力和 ABCG2 亲和力。在存在和不存在 Ko143（一种 ABCG2 选择性抑制剂）的情况下，用 FL118 处理有或没有 ABCG2 过表达的结肠癌细胞和肺癌细胞，或者通过基因调节 ABCG2 表达来处理。使用两种不同的体内人类肿瘤动物模型，我们进一步评估了 FL118 与伊立替康相比是否可以延长进展时间。最后，我们研究了一系列具有 B 环取代的 FL118 类似物以提高 ABCG2 敏感性。 ABCG2 的药理学抑制和遗传调节都表明，与 SN-38 相比，FL118 能够绕过 ABCG2 介导的耐药性。与伊立替康相比，FL118 在两种体内模型中的进展时间均延长了 50% 以上。最后，我们观察到具有极性取代的 FL118 类似物对 ABCG2 具有更高的亲和力，这表明 FL118 的非极性性质在绕过 ABCG2 介导的耐药性中发挥了作用。我们的结果表明，与 SN-38 和拓扑替康相比，FL118 是 ABCG2 的较差底物，可以有效克服 ABCG2 介导的耐药性。我们的研究结果扩展了 FL118 的独特性，并支持 FL118 的持续开发，作为对 ABCG2 高表达导致的药物难治性癌症患者的有吸引力的治疗选择。本文的在线版本 (doi:10.1186/s12943-015-0362-9) 包含补充材料，可供授权用户使用。
Irinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions. Colon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity. Both pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance. Our results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2. The online version of this article (doi:10.1186/s12943-015-0362-9) contains supplementary material, which is available to authorized users.
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影响因子：
120.1
作者：
Galsky, Matthew D.;Dritselis, Argyris;Oh, William K.
通讯作者：
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影响因子：
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通讯作者：
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