Potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice
Potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice
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DOI：
10.1158/1078-0432.ccr-05-0229
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
McDaid, HM
中科院分区：
文献类型：
--
作者：
Huang, GS;Lopez-Barcons, L;McDaid, HM
目的：探讨地德莫里特与紫杉醇联合用药对人卵巢癌细胞及卵巢癌体内模型的影响。实验设计：采用联合指数法评价紫杉醇与地德莫里酯对人卵巢SKOV-3癌细胞的相互作用。数据与细胞周期分布和caspase激活的改变相关。此外，将携带SKOV-3异种移植物的小鼠分别给予紫杉醇、迪德莫里特或两种药物联合治疗，以评估该联合治疗的抗肿瘤疗效和毒性。采用Matrigel栓试验和CD31免疫组化评价抗血管生成作用。结果：紫杉醇和迪德莫内酯在一定浓度和摩尔比范围内协同作用，引起卵巢癌细胞药物诱导的非整倍体。在携带SKOV-3异种移植物的小鼠中，联合用药明显优于单独用药，并诱导肿瘤消退，无明显毒性。CD31免疫组织化学分析和Matrigel栓分析显示，与单独用药相比，联合用药小鼠血管形成减少。结论：紫杉醇和地dermolide在细胞中的协同作用在药物浓度下是最有效的，导致药物诱导的非整倍体而不是有丝分裂停止。此外，在卵巢癌动物模型中，这是一种耐受性良好的组合，可诱导肿瘤消退并抑制血管生成。这些数据证实了这一组合的效力，并支持同时使用低剂量紫杉醇和地德莫里作为癌症治疗的潜在用途。
Purpose: To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma.Experimental Design: The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects.Results: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone.Conclusions: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.