Synergy of Nab-paclitaxel and Bevacizumab in Eradicating Large Orthotopic Breast Tumors and Preexisting Metastases
Synergy of Nab-paclitaxel and Bevacizumab in Eradicating Large Orthotopic Breast Tumors and Preexisting Metastases
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DOI：
10.1593/neo.101490
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发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Ran, Sophia
中科院分区：
文献类型：
--
作者：
Volk, Lisa D.;Flister, Michael J.;Ran, Sophia
引言：转移性疾病患者被认为是不可治愈的。我们以前表明，nabpaclitaxel（纳米粒白蛋白包埋的紫杉醇）与抗血管内皮生长因子A（VEGF-A）抗体，贝伐单抗，根除原位小尺寸乳腺肿瘤和转移。在这里，我们在两个晚期（450-600 mm（3））乳腺肿瘤模型中评估了这种疗法，并描述了肿瘤耐药的VEGF-A依赖性机制。方法：用盐水、白蛋白结合型紫杉醇（10或30 mg/kg）、贝伐单抗（4 mg/kg）或组合药物治疗具有经谷胱甘肽转移酶标记的晚期MDA-MB-231和MDA-MB-435肿瘤的小鼠。通过荧光素酶测定来测量淋巴和肺转移。通过ELISA、Western blot和免疫组织化学检测促炎和存活途径。结果：白蛋白结合型紫杉醇对原发性肿瘤的抑制率为70%~ 90%，但对转移无影响。同时给予贝伐珠单抗使应答率增加至99%，包括同时给予30 mg/kg白蛋白结合型紫杉醇治疗的MDA-MB-231荷瘤小鼠中71%的完全应答。该组合方案显著减少或消除了MDA-MB-231和MDA-MB-435模型中预先存在的淋巴和远端转移。其机制涉及紫杉醇诱导的NF-κ B通路，其上调VEGF-A和其他肿瘤促生存蛋白。结论：贝伐单抗可预防nab-紫杉醇通过激活NF-κ B通路促进的肿瘤复发和转移。高剂量白蛋白结合型紫杉醇联合治疗显示出根除晚期原发性肿瘤和既存转移的潜力。这些发现有力地支持将该方案转化为临床。
INTRODUCTION: Patients with metastatic disease are considered incurable. We previously showed that nabpaclitaxel (nanoparticle albumin-embedded paclitaxel) combined with anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, eradicates orthotopic small-sized breast tumors and metastasis. Here, we assessed this therapy in two models of advanced (450-600 mm(3)) breast tumors and delineated VEGF-A-dependent mechanisms of tumor resistance. METHODS: Mice with luciferase-tagged advanced MDA-MB-231 and MDA-MB-435 tumors were treated with saline, nab-paclitaxel (10 or 30 mg/kg), bevacizumab (4 mg/kg), or combined drugs. Lymphatic and lung metastases were measured by luciferase assay. Proinflammatory and survival pathways were measured by ELISA, Western blot and immunohistochemistry. RESULTS: Nab-paclitaxel transiently suppressed primary tumors by 70% to 90% but had no effect on metastasis. Coadministration of bevacizumab increased the response rate to 99%, including 71% of complete responses in MDA-MB-231-bearing mice treated concurrently with 30 mg/kg of nab-paclitaxel. This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA-MB-231 and MDA-MB-435 models. The mechanism involves paclitaxel-induced NF-kappa B pathway that upregulates VEGF-A and other tumor prosurvival proteins. CONCLUSIONS: Bevacizumab prevents tumor recurrence and metastasis promoted by nab-paclitaxel activation of NF-kappa B pathway. Combination therapy with high-dosed nab-paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases. These findings strongly support translating this regimen into clinics.