Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma.
Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma.
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DOI：
10.1186/s12885-018-4738-2
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发表时间：
2018-10-11
期刊：
影响因子：
3.8
通讯作者：
Han YW
中科院分区：
文献类型：
--
作者：
Qin RS;Zhang ZH;Zhu NP;Chen F;Guo Q;Hu HW;Fu SZ;Liu SS;Chen Y;Fan J;Han YW
常规化疗通常用于治疗非小细胞肺癌（NSCLC），但它会增加治疗耐药性。相比之下，节拍化疗（MET）是基于低剂量的频繁给药，导致抑制新血管形成和诱导肿瘤休眠。本研究旨在评价MET长春瑞滨（NVB）联合血管生成抑制剂（Endostar）的抑制作用、不良事件和潜在机制。采用流式细胞术、Western blot、免疫荧光染色和酶联免疫吸附试验（ELISA）检测循环内皮祖细胞（CEPs）、凋亡率、CD 31、血管内皮生长因子（VEGF）、缺氧诱导因子-1 α（HIF-1α）的表达。部分动物还采用微量氟-18-脱氧葡萄糖PET/CT（18F-FDG PET/CT）观察，通过比较SUVmax值确定变化。此外，进行肝、肺、肾和心脏的白色血细胞（WBC）计数和H& E染色切片以监测毒性评估。我们发现MET NVB + Endo治疗在抑制肿瘤生长，降低CD 31，VEGF，HIF-1α和CEP表达，减少副作用，诱导凋亡，如Bcl-2，Bax和caspase-3表达方面最有效。最大耐受剂量的NVB联合Endostar（MTD NVB + Endo）给药表现出相似的抗肿瘤作用，包括微量氟-18-脱氧葡萄糖PET/计算机断层扫描（18F-FDG PET/CT）成像显示的葡萄糖代谢变化，但血管生成未受到抑制。与单药相比，联合用药的抗肿瘤效果更好。这些结果表明，MET NVB与Endo组合显著增强了人肺癌异种移植模型中的抗肿瘤和抗血管生成反应，而没有明显的毒性。
Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar). Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments. We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects. These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.
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