The Tyrosine Kinase Inhibitor E-3810 Combined with Paclitaxel Inhibits the Growth of Advanced-Stage Triple-Negative Breast Cancer Xenografts
The Tyrosine Kinase Inhibitor E-3810 Combined with Paclitaxel Inhibits the Growth of Advanced-Stage Triple-Negative Breast Cancer Xenografts
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DOI：
10.1158/1535-7163.mct-12-0275-t
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发表时间：
2013-02-01
影响因子：
5.7
通讯作者：
Damia, Giovanna
中科院分区：
文献类型：
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作者：
Bello, Ezia;Taraboletti, Giulia;Damia, Giovanna
E-3810是一种新型小分子，以nmol/L的浓度抑制VEGF受体-1、-2和-3和成纤维细胞生长因子受体-1酪氨酸激酶，目前处于临床II期。在临床前研究中，当作为多种人类异种移植物的单一疗法时，它具有广谱的抗肿瘤活性。我们在此研究了E-3810与不同细胞毒药物联合在MDA-MB-231三阴性乳腺癌异种移植模型中的活性。该分子可与5-氟尿嘧啶、顺铂和紫杉醇安全联合使用。e -3810-紫杉醇联合用药显示出显著的活性，肿瘤消退完全、持久；在另一种三阴性乳腺异种移植物MX-1中也证实了该组合的抗肿瘤活性。活性优于紫杉醇+布里伐尼和紫杉醇+舒尼替尼的组合。药代动力学研究表明，该组合的额外抗肿瘤活性并非由于较高的紫杉醇肿瘤水平，事实上，在使用所有三种激酶抑制剂预处理的小鼠中，紫杉醇肿瘤水平较低，而且紫杉醇血浆水平排除了药物可用性降低的因素。药理学研究表明，E-3810、布里瓦尼和舒尼替尼单独或与紫杉醇联合使用可减少血管数量，但不改变血管成熟。肿瘤IV型胶原蛋白的减少和血浆IV型胶原蛋白的增加，与基质金属蛋白酶（MMP），特别是宿主MMP-9的增加相关，表明E-3810引起的细胞外基质的蛋白水解重塑，与紫杉醇对肿瘤细胞的细胞毒性作用（caspase-3/7活性）相结合，可能是它们联合作用的显著原因。这些数据支持E-3810联合常规化疗的治疗潜力。巨蟹座；12 (2);131 - 40。AACR (C) 2012。
E-3810 is a novel small molecule that inhibits VEGF receptor-1, -2, and -3 and fibroblast growth factor receptor-1 tyrosine kinases at nmol/L concentrations currently in phase clinical II. In preclinical studies, it had a broad spectrum of antitumor activity when used as monotherapy in a variety of human xenografts. We here investigated the activity of E-3810 combined with different cytotoxic agents in a MDA-MB-231 triple-negative breast cancer xenograft model. The molecule could be safely administered with 5-fluorouracil, cisplatin, and paclitaxel. The E-3810-paclitaxel combination showed a striking activity with complete, lasting tumor regressions; the antitumor activity of the combination was also confirmed in another triple-negative breast xenograft, MX-1. The activity was superior to that of the combinations paclitaxel+brivanib and paclitaxel+sunitinib. Pharmacokinetics studies suggest that the extra antitumor activity of the combination is not due to higher paclitaxel tumor levels, which in fact were lower in mice pretreated with all three kinase inhibitors, and the paclitaxel plasma levels excluded reduced drug availability. Pharmacodynamic studies showed that E-3810, brivanib, and sunitinib given as single agents or in combination with paclitaxel reduced the number of vessels, but did not modify vessel maturation. Reduced tumor collagen IV and increased plasma collagen IV, associated with increased matrix metalloproteinases (MMP), particularly host MMP-9, indicate a proteolytic remodeling of the extracellular matrix caused by E-3810 that in conjunction with the cytotoxic effect of paclitaxel on the tumor cells (caspase-3/7 activity) may contribute to the striking activity of their combination. These data support the therapeutic potential of combining E-3810 with conventional chemotherapy. Mol Cancer Ther; 12(2); 131-40. (C)2012 AACR.