Investigation On The Antitumor Effects And Mechanisms Of EGFR Tyrosine Kinase Inhibitors AL68 Series

Objective: This study was conducted to find out active compounds with potent tumor inhibition ability from 17 compounds of AL68 series screening. Our research also included the further evaluation on antitumor effects of active compounds in vitro and its mechanisms.Methods: (1) The antiproliferative effect of AL68 series against A549 and Lovo in vitro was observed by MTT assay. (2) the antitumor effect of active compounds in vivo was evaluated with the model of nude mice bearing A431 xenografts.(3)The antiproliferative effect of AL6801 and AL6802 against 7 solid tumor cell lines in vitro was examined with MTT assay.(4) The effect of active compounds on EGFR tyrosine kinases phosphorylation was determined by ELISA assay. (5) The effect of AL6801 and AL6802 on cell cycle distribution and induction of apoptosis was assessed by flow cytometry analysis.Results: (1)After preliminary screening in vitro, 7 active compounds with inhibitory effect on A549 and Lovowere identified: AL6800, AL6801, AL6802, AL6815, AL6817, AL6818, AL6819. And AL6801 showed significant growth inhibitive effect on A549 while AL6802 showed significant growth inhibitive effect on Lovo. (2) All of the 7 active compounds inhibited A431xenografts growth and differed in inhibition degree. Notably, tumor inhibition rate of AL6801 group and AL6802 group were 63.09% and 52.19% at the dose of 50mg/kg respectively. There were significant differences in the tumor weight and volume between these two groups and negative control group (p<0.01). In addition, during the course of agent administration, neither reduction in body weight nor other relevant toxicity was observed in sample group as compare with negative control group. (3) In the further study, AL6801 and AL6802 were observed to inhibit cell proliferation in a dose-dependent manner in 7 tumor cell lines while differd in inhibition degree. The results suggested that there were no correlation between expression level of EGFR and sensitivity to EGFR-TKIs. In addition, concentration-...