Antitumor Effects Of Gefitinib-endostar Combination On EGFR-mutated Lung Cancer In Vitro And Vivo

BACKGROUND and OBJECTIVE:About 20% of advanced none small-cell lung cancer(NSCLC)cases harbor somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR)gene.In these patients,the standard first-line treatments are the EGFR-tyrosine kinase inhibitors.Most of these patients initially respond well to EGFR-tyrosine kinase inhibitors treatment;however,patients develop acquired resistance approximately 1 year after initial therapy.In recent years,mang studys combinated EGFR-TKIs with other drugs to treat EGFR mutation NSCLC and achived more effective results than single drug treatment.It is suggested that combination treatment may improve the prognosis of EGFR gene mutation NSCLC patients.Gefitinib is the first generation of reversible EGFR-TKIs,and was approved for the first line treatment of NSCLC patients with EGFR gene mutations.Endostar(re-endostatin)is an multiple targets anti-angiogenesis drug,and was approved to combinate with NP chemotherapy regimen to treat stage III / IV NSCLC patients.The purpose of our study is to investigate the anticancer effects of gefitinib-endostar combination in EGFR mutation NSCLC in vitro and in vivo.Hence,combined treatment of gefitinib with endostar may form a basis to develop a more effective therapy for NSCLC harboring EGFR mutations.METHODS:1.HCC827 cells(exon 19 deletion EGFR)and A549(wild-type EGFR)cells were choosed for our study.The two cell lines were treated with different drugs for72 hours.Effects of gefitinib and/or endostar on the survival of NSCLC cells were determined using the MTT reduction assay.2.Cell apoptosis was detected using annexinV-FITC/PI Apoptosis Detection kit by flow cytometry.3.Subcutaneous lung cancer xenograft model of BALB/c-nu mice was established,then the mice were randomly divided into control group(oral gavage with 0.9% NaCl,intraperitoneal injection with0.9% NaCl,d1-30),gefitinib group(oral gavage with gefitinib solution,intraperitoneal injection with 0.9% NaCl,d1-30),endostar group(oral gavage with 0.9%NaCl,intraperitoneal injection with re-endostatin injection,d1-30),gefitinib-endostar combination group(oral gavage with gefitinib solution,intraperitoneal injection with re-endostatin injection,d1-30),there were five mice in each group.After drug administration,the volume of xenograft tumor and the weight in different groups was measured dynamically.Tumor weights were observed to calculate the inhibitory rate after thirty days of administration.RESULTS:1.The rate of cell proliferation in gefitinib combined with endostar group was lower than that in the gefitinib group for HCC827 cells(P<0.05).There were no difference of cell viability between gefitinib combined with endostar group and gefitinib group in A549 cells(P>0.05).2.The apoptotic rate in gefitinib combined with endostar group was higher than that in gefitinib group(P<0.05)and was significantly higher than that in endosta group as well as control group(P<0.001).3.The tumor growth was significantly inhibited after treatment with gefitinib combined with endostar in mice lung cancer xenograft model.The tumor inhibitory rate was much higher in the gefitinib combined with endostar group than in the other groups(P<0.05).CONCLUSION:In NSCLC cells harboring EGFR mutations,combination gefitinib-endostar treatment led to synergistic cell proliferation,but there was minimal efficacy in NSCLC cells with wild-type EGFR.In NSCLC cells harboring EGFR mutations,treating with gefitinib combined with endostar also led to synergistic cell apoptosis.In xenograft models,combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment.It reckons thatgefitinib-endostar combination may be a promising therapy for NSCLC patients with EGFR gene mutations.