Antitumor effects of Endostar(rh-endostatin) combined with gemcitabine in different administration sequences to treat Lewis lung carcinoma

Yuan Li,1 Pan Huang,2 Hongju Peng,1 Hongcheng Yue,1 Min Wu,1 Shanshan Liu,1 Rongsheng Qin,1 Juan Fan,1 Yunwei Han11The Oncology Department, Affiliated Hospital of Southwest Medical University, Lu Zhou, Si Chuan 646000, People’s Republic of China; 2Neurology Department, Deyang People’s Hospital, Deyang, Sichuan 618000, People’s Republic of ChinaBackground: Endostatin therapy is known to efficiently inhibit angiogenesis and growth of endothelial cells. Nonetheless, the antitumor mechanisms of endostatin combined with chemotherapy remain to be elucidated.Methods: In our study, a Lewis lung carcinoma transplant mouse model was established and treated with the recombinant human [rh]-endostatin, Endostar, combined with gemcitabine at different sequences. 18F-FDG PET/CT imaging was performed to monitor tumor growth, and hypoxia was examined using an oxygen microelectrode. Vascular endothelial growth factor (VEGF) and alpha smooth muscle actin (α-SMA) levels were detected via immunohistochemistry analysis and cell cycle distributions were analyzed by flow cytometry.Results: Endostar decreased VEGF expression, improved hypoxia, and influenced cell cycle distributions. Simultaneous treatment of Endostar and gemcitabine displayed significantly tumor inhibition, possessed the lowest uptake of FDG, improved oxygen partial pressure, decreased expression of VEGF, and increased pericyte coverage. Cell cycle analysis demonstrated that cells accumulated in the S phase following gemcitabine treatment and G0/G1 arrest occurred following Endostar treatment. An increase of cells in G0/G1 phase was observed following treatment with Endostar and gemcitabine.Conclusions: Our study suggests that the combination therapy of Endostar with gemcitabine simutaneously may optimally enhance their individual antitumor effects.Keywords: recombinant human endostatin, gemcitabine, antiangiogenic, combination therap