Treatment of malignant pleural effusion in non-small cell lung cancer with VEGF-directed therapy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a critical regulator of malignant pleural effusion (MPE) in non-small-cell lung cancer (NSCLC). Bevacizumab (BEV) and apatinib (APA) are novel VEGF blockers that inhibit lung cancer cell proliferation and the development of pleural effusion. METHODS: In this study, we established Lewis lung cancer (LLC) xenograft mouse models to compare the therapeutic effect of APA and BEV in combination with cisplatin (CDDP) against MPE. The anti-tumour and anti-angiogenic effects of this combination therapy were evaluated by 18F-FDG PET/CT imaging, TUNEL assay and Immunohistochemistry. RESULTS: The triple drug combination significantly prolonged the overall survival of the tumour-bearing mice by reducing MPE and glucose metabolism and was more effective in lowering VEGF/soluble VEGFR-2 levels in the serum and pleural exudates compared to either of the monotherapies. Furthermore, CDDP + APA + BEV promoted in vivo apoptosis and decreased microvessel density. CONCLUSIONS: Mechanistically, LLC-induced MPE was inhibited by targeting the VEGF-MEK/ERK pathways. Further studies are needed to establish the synergistic therapeutic effect of these drugs in NSCLC patients with MPE.KEY MESSAGESCombined treatment of MPE with apatinib, bevacizumab and cisplatin can prolong the survival time of mice, reduce the content of MPE, decrease the SUVmax of thoracic tumour tissue, down-regulate the content of VEGF and sVEGFR-2 in serum and pleural fluid, and promote the apoptosis of tumour cells. Angiogenesis and MPE formation can be inhibited by down-regulation of HIF-1α, VEGF, VEGFR-2, MEK1 and MMP-2 molecular signalling pathway proteins.

Anlotinib Suppresses Colorectal Cancer Proliferation and Angiogenesis via Inhibition of AKT/ERK Signaling Cascade.

BACKGROUND: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor, with very good anti-tumor activity against a variety of solid tumors. However, its effect on colorectal cancer (CRC) is not yet clearly understood. The objective of this study was to investigate the anti-tumor effect and underlying mechanism of anlotinib in the pathogenesis of CRC. MATERIALS AND METHODS: Effects of anlotinib on CT26 cells proliferation and microvessel formation in endothelial cells were determined by MTT assay and tube formation assay. Cell migration and invasion were analyzed by using the wound healing assay and transwell assay. Cell cycle and apoptosis were detected by flow cytometry. A CRC xenograft mouse model was used for conducting in-vivo studies to verify the effect of anlotinib. The expression of Ki-67 and CD31 in the tumor tissue was detected by immunohistochemistry and protein expression was measured by Western blot. RESULTS: In-vitro studies revealed that anlotinib inhibited the proliferation, migration, and invasion of CT26 cells and the tube formation of HUVECs in a dose-dependent manner. Anlotinib also significantly induced cell apoptosis and G2/M arrest. It effectively inhibited tumor growth and prolonged survival time in the CRC xenograft mouse model. Immunohistochemical analysis of the tumor tissue revealed that anlotinib downregulated CD31 and Ki-67 which are the biomarkers of microvessel density and proliferation. Furthermore, anlotinib was able to inhibit the activation of VEGFR-2/AKT and FGFR, PDGFRß and their downstream signaling ERK. CONCLUSION: The findings of the present study suggested that anlotinib suppressed cell proliferation and angiogenesis via inhibition of AKT/ERK signaling pathway in colorectal cancer and could be a novel therapeutic strategy for treatment of CRC.

Comparison of different images in gross target volume delineating on VX2 nasopharyngeal transplantation tumor models.

Background: To determine the optimum conditions for diagnosis of nasopharyngeal carcinoma, we established VX2 rabbit model to delineate gross target volume (GTV) in different imaging methods. Methods: The orthotopic nasopharyngeal carcinoma (NPC) was established in sixteen New Zealand rabbits. After 7-days inoculation, the rabbits were examined by CT scanning and then sacrificed for pathological examination. To achieve the best delineation, different GTVs of CT, MRI, 18F-FDG PET/CT, and 18F-FLT PET/CT images were correlated with pathological GTV (GTVp). Results: We found 45% and 60% of the maximum standardized uptake value (SUVmax) as the optimal SUV threshold for the target volume of NPC in 18F-FDG PET/CT and 18F-FLT PET/CT images, respectively (GTVFDG45% and GTVFLT60%). Moreover, the GTVMRI and GTVCT were significantly higher than the GTVp (P ≤ 0.05), while the GTVFDG45% and especially GTVFLT60% were similar to the GTVp (R = 0.892 and R = 0.902, respectively; P ≤ 0.001). Conclusions: Notably, the results suggested that 18F-FLT PET/CT could reflect the tumor boundaries more accurately than 18F-FDG PET/CT, MRI and CT, which makes 18F-FLT PET-CT more advantageous for the clinical delineation of the target volume in NPC.