The Effect Of Low-Dose Cyclophsphamide On HIF-1α/VEGF And HIF-1α/Survivin Pathway Of Implanted Human Lung Carcinoma In Nude Mice

Objective:To evaluate the effect of low-dose cyclophosphamide(CTX )on angiogenesis and apoptosis of implanted human lung carcinoma in nud- e mice. investigate its antitumor effect and toxicity, further explore the effet of HIF-1α/VEGF pathway and HIF-1α/Survivin pathway in treatment of lu- ng carcinoma by mentronomic chemotherapy, so as to search for new me- chanisms and provide theory for lung carcinoma therapy.Methods : cell line A549 of lung adenocarcinoma was cultivated and BALB/C nude mice bearing A549 lung carcinoma were randomized into three groups: low—dose metronomic(LDM) CTX treatment group,maxim- um tolerate dose(MTD)CTX treatment group and normal saline control gr- oup,then we investigate its antitumor effect and body weight change.At the end of the experiment,Tumor microvascular density(MVD),hypoxia-indu- cible factor 1 alpha (HIF-1α),vascular endothelial growth factor (VEGF) and Survivin(an inhibitor apoptosis protein)were detected by immunohist- ochemical staining.And apoptosis was measured by TUNEL.At last, HIF- 1αand VEGF genetic transcription were detected by hybridization in situ .Results: (1) In the mice received LDM CTX therapy,growth delays of tumor were found and without apparent body weight loss, compared with those in MTD CTX group and control group(P〈0.05). (2) MVD of tumors were much lower in mice received continuous low—dose CTX therapy tha- n those in MTD CTX group and control group(P〈0.01 ).In low—dose CTX therapeutic group, HIF-1αand VEGF expression were also decreased(P〈0.01). (3) In LDM CTX group, apoptotic cell(AI) were increased than those in other two group(sP〈0.05),and Survivin expression of tumors were much lowe(rP〈0.01). (4) In low—dose CTX therapeutic group, the mRNA expression of HIF-1αand VEGF were also decreased than other two groups(P〈0.05 ). (5) HIF-1αwas correlated with VEGF,MVD(P〈0.01), and HIF-1αwas correlated with Survivin,AI(P〈0.01).Conclusion: The continuous low—dose regimen of CTX increases the efficacy of targeting the tumor microvasculature,inhibits the growth of im- planted lung cancer and increases the efficacy of cell apoptosis,which may be due to the down regulation of HIF-1αpathway.