Inhibition of Multidrug Transporter in Tumor Endothelial Cells Enhances Antiangiogenic Effects of Low-Dose Metronomic Paclitaxel
Inhibition of Multidrug Transporter in Tumor Endothelial Cells Enhances Antiangiogenic Effects of Low-Dose Metronomic Paclitaxel
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DOI：
10.1016/j.ajpath.2014.10.017
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发表时间：
2015-02-01
影响因子：
6
通讯作者：
Hida, Kyoko
中科院分区：
文献类型：
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作者：
Akiyama, Kosuke;Maishi, Nako;Hida, Kyoko
肿瘤血管生成在肿瘤的进展和转移中起着重要作用。肿瘤内皮细胞（TECs）是最近发展起来的抗血管生成化疗的治疗靶点，目前正在临床研究中，并取得了令人鼓舞的结果。低剂量化疗是指长期使用相对低剂量的化疗药物，已被提出用于各种类型癌症的肿瘤血管生成。虽然低剂量化疗的疗效已在几种临床模型中得到证实，但一些研究表明对恶性肿瘤的治疗效果不足。作为治疗失败的一种可能机制，人们认为肿瘤细胞可能对这种治疗产生耐药性。然而，tec的耐药也可能是由于肿瘤细胞对低剂量化疗的另一种耐药机制。我们在其他地方报道过，tec对抗癌药物紫杉醇有耐药性，紫杉醇是一种有丝分裂抑制剂，伴随p糖蛋白上调。维拉帕米，一种p糖蛋白抑制剂，在体外消除了TEC耐药性。在本研究中，我们在临床前小鼠黑色素瘤异种移植模型中证明，维拉帕米联合给药增强了低剂量紫杉醇同时抑制肿瘤血管生成的效果。此外，维拉帕米联合用药可减少肺转移。这些结果表明，抑制TECs中的p -糖蛋白可能是针对TECs的低剂量化疗的新策略。
Tumor angiogenesis plays an important role in tumor progression and metastasis. Tumor endothelial cells (TECs) are a therapeutic target of antiangiogenic chemotherapy that was recently developed and is currently being investigated in the clinic with promising results. Low-dose chemotherapy, which is the Long-term administration of relatively Low doses of chemotherapeutic agents, has been proposed for targeting tumor angiogenesis in various types of cancers. ALthough the efficacy of low-dose chemotherapy has been confirmed in several clinical models, some studies show insufficienttherapeutic effect for malignant cancers. As a possible mechanism of the treatment failure, it has been considered that tumor cells may acquire resistance to this therapy. However, drug resistance by TECs may also be due to another mechanism for resistance of tumor cells to low-dose chemotherapy. We reported elsewhere that TECs were resistant to the anticancer drug paclitaxel, which is a mitotic inhibitor, concomitant with P-glycoprotein up-regulation. Verapamil, a P-glycoprotein inhibitor, abrogated TEC resistance in vitro. Herein, we demonstrated that verapamil coadministration enhanced the effects of Low-dose paclitaxel concomitant with inhibiting tumor angiogenesis in a preclinical in vivo mouse melanoma xenograft model. Furthermore, verapamil coadministration reduced lung metastasis. These results suggest that inhibiting P-gLycoprotein in TECs may be a novel strategy for low-dose chemotherapy targeting TECs.