Abstract
BackgroundConventional 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).MethodsCirculating 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.ResultsWe 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.ConclusionThese 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.
Highlights
Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) it increases therapeutic resistance
These results indicated that the metronomic chemotherapy (MET) NVB + Endo treatment group had a similar effect as the Maximum tolerated dose (MTD) NVB + Endo group, and had an increased tumor growth inhibition effect compared with the other treatment groups tested
In the present study, we investigated the impact of MET NVB and/or Endostar on the frequency of circulating endothelial progenitor cells (CEPs), expression of CD31, vascular endothelial growth factor (VEGF), and HIF-1α in tumor-bearing mice
Summary
Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) it increases therapeutic resistance. Previous studies have shown that metronomic oral Vinorelbine can be safely used in elderly patients with advanced NSCLC, allowing for long-term disease stabilization combined with optimal patient compliance [4, 5]. Together, these studies, including numerous preclinical and clinical trials, provide accumulative evidence that MET maintains the therapeutic response, minimizes relapse after conventional chemotherapy, and overcomes resistance [1,2,3]
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