Efficacy of granulocyte-macrophage colony-stimulating factor combined with metronomic paclitaxel in the treatment of Lewis lung carcinoma transplanted in mice.

Nengping Zhu,Rongsheng Qin,Shaozhi Fu,Shanshan Liu,Juan Fan,Yunwei Han,Yue Chen,Qin Zhang

doi:10.18632/oncotarget.23530

Nengping Zhu, Rongsheng Qin + Show 6 more

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https://doi.org/10.18632/oncotarget.23530

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Abstract

Metronomic chemotherapy in combination with immunotherapy is an attractive approach in cancer therapy. The purpose of the present study was to investigate the anti-tumor effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with metronomic paclitaxel (MET PTX) on Lewis lung carcinoma transplanted in mice. In the present study, tumor-bearing mice survival time and tumor growth were monitored. The day after the end of the treatment, white blood cells were counted, and the number and maturation of dendritic cell were determined by flow cytometry. Besides, microvessel density and tumor cell proliferation were determined by immunohistochemistry, while apoptosis was determined by TUNEL (Terminal deoxynucleotidyl transferase-mediated nick end labeling) assay. Micro 18F-FDG PET/CT (18F-Fluorodeoxyglucose positron emission tomography/computed tomography) was used to obtain SUVmax values. White blood cells reduction was not observed in the mice treated with GM-CSF combined with MET PTX. Moreover, GM-CSF combined with MET PTX further reduced proliferation and microvessel density, promoted tumor apoptosis, increased the dendritic cells number and induced their maturation, with concomitant delay in tumor growth and improved survival. Taken together, GM-CSF combined with MET PTX exerted a synergistic anti-tumor effect against lung cancer in a mouse model through an antiangiogenic activity and inducing dendritic cells maturation without exerting pronounced adverse effects. Hence, combined metronomic chemotherapy and immunotherapy could be a potential strategy for the treatment of patients with advanced lung cancer.

Highlights

Lung cancer is the leading cause of cancer related deaths in China with increasing incidence and mortality [1]
Mice treated with metronomic paclitaxel (MET PTX) or maximum tolerated dose (MTD) PTX could delay the tumor growth compared to the control group (P < 0.05), no significant difference was observed between the two groups
We evaluated the hypothesis that granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with MET PTX might provide an anti-tumor effect dramatically enhanced over GM-CSF or MET PTX alone and superior than GM-CSF combined with MTD PTX

Summary

Introduction

Lung cancer is the leading cause of cancer related deaths in China with increasing incidence and mortality [1]. The most common lung cancer form (83%) is nonsmall-cell lung cancer (NSCLC). Because NSCLC at early stage lacks specific symptoms, 57% of these patients are diagnosed at an advanced stage [2]. Conventional chemotherapy remains the standard treatment for the non-selective advanced NSCLC, which means a cyclic administration of chemotherapeutic drugs in a maximum tolerated dose (MTD) to exert its anti-tumor effect [3]. MTD chemotherapy can systemically kill most tumor cells, simultaneously destroying non-tumor cells, leading to immunosuppression and other dose-limiting www.impactjournals.com/oncotarget side effects. Most patients with advanced NSCLC are not able to tolerate the adverse effects of MTD chemotherapy, resulting in poor prognosis. There is an urgent need for more effective and tolerable treatments to improve the quality of life and prolong the survival time

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