低氧与肿瘤多药耐药.pptx

低氧与肿瘤多药耐药低氧与肿瘤多药耐药Hypoxia and Multidrug Resistance Professor Chen bao-an Dept.of Hematology Affiliated Zhongda Hospital Southeast University ContentResearch backgroundResearch progressionClinical applicationJob from our own LabPart IResearch BackgroundReason of Deathu Multidrug Resistance(MDR)u Transfer u Complication u Tumor relapseu Others90%Mechanism of Multidrug Resistance Michael M.et al;nature reviews 2002,2:48-57Cellular Factors of Cause MDR Michael M.et al;nature reviews 2002,2:48-57Focus onHow to raise accumulation of chemotherapy drug in cell?How to decrease the toxicity function of chemotherapy drug?Research Fieldu Structure Genetic alterations Epigenetic changes u Function Immune Factor:antibody、immune cell、cell factor Gene Technology:RNAi、AOD、Ribozyme Hypoxia(hypoxia induce factor-1,HIF-1)HIF-1a a StructureHypoxia and HIF-1a aBrian Keith;et al;Cell 129,2007,May(4):465-476HiF-1a a and ApoptosisConclusion of Part IHypoxia play roles in MDR failureTarget HIF-1 gene therapy should be available for MDR patient Part Research Progression of both HIF-1 and MDR丁震宇丁震宇,梁后杰梁后杰 免疫学杂志免疫学杂志 2008HIF-1a与P-gp 在结肠癌组织表达存在相关性两者相互作用共同参与结肠癌多药耐药的发生HIF-1a a与与P-gp 在结肠癌组织中的表达及意义在结肠癌组织中的表达及意义Min Liu,et al,JBC,2007 onlinePO2-dependent differential regulation of multi-drug resistance 1 gene expression by the c-Jun NH2-terminal Kinase PathwayThe JNK pathway plays PO2-dependent different roles in regulating MDR1 expression down-regulation of MDR1 expression in normoxia.up-regulation of MDR1 expression in hypoxia.JNK down-regulates MDR1 expression in normoxia and up-regulates MDR1 expression in hypoxiaResearch ResultsXianrang,et al Cancer Chemother Pharmacol,2006 online Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1 geneHypoxia-induced chemoresistance to cisplatin and doxorubicin is through the HIF-1a pathway.Combining delivery of HIF-1 RNAi lentiviral vector with cisplatin-related chemotherapy regimens may enable more strategy for NSCLC therapy.Effect of O2 concentration on survival of HIF-1 gene silencing NSCLC cells to chemotherapy drugPart Clinical applicationRoy Vergis,Lancet Oncol.2008 onlineIntrinsic markers of hypoxia and angiogenesis in relation to the outcome of radical treatment of prostate cancer.Increased expression of HIF-1a a,identifies patients at high risk of biochemical failure.Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment:a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study(A)HIF-1 alpha score 4(B)HIF-1 alpha score 1(C)HIF-1 alpha score 0(A)Radiotherapy cohort.(B)Radical prostatectomy cohortKourti,Int J Hematol.2007 online MDR1 expression was significantly higher at relapse than at diagnosis Evaluation of MDR1 expression at diagnosis of childhood ALL may contribute to the early identification of patients at risk of treatment failureExpression of Multidrug Resistance 1(MDR1),Multidrug ResistanceRelatedProtein 1(MRP1),Lung Resistance Protein(LRP),and Breast CancerResistance Protein(BCRP)Genes and Clinical Outcome in Childhood AcuteLymphoblastic LeukemiaRelative messenger RNA expression by the MDR1,MRP1,LRP,and BCRP genes in ALLActivate Drug of Hypoxia醌类醌类:如丝裂霉素如丝裂霉素C、E09 芳香族芳香族N-氧化物氧化物:TPZ 脂肪族脂肪族N-氧化物氧化物:AQ4N 硝基杂环类硝基杂环类:细胞毒剂细胞毒剂CB1954、SN-3862 缺氧标志物缺氧标志物NITP、SR4554Inhibition of HIF-1a u 拓扑异构酶拓扑异构酶-1 抑制剂抑制剂u 微管靶向因子微管靶向因子u 信号转导抑制剂信号转导抑制剂u YC-1Reversal Drug of MDRGergely Szakacs;et al;Nature,2006,March(5),219-235Gergely Szakacs;et al;Nature,2006,March(5),219-235Part Our Work Relative：HiF-1a、MDR and Outcome；Blood SampleMechanism：Adjust function of HiF-1a to MDR；in vivo、in vitroChemotherapeutic Drug：Raise effect 5-bromotetrandrineThanks your guidance