低氧與腫瘤多藥耐藥課件

1、低氧與腫瘤多藥耐藥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 Death Multidrug Resistance (MDR) Transfer Comp

2、lication Tumor relapse 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 2002,2:48-57HIF-1a StructureHypoxia and HIF-1aBrian Keith; et al; Cell 129, 2007,May(4):465-476HiF-1a and ApoptosisMin Liu, et

3、 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 express

4、ion 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 gen

5、eHypoxia-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

6、cells to chemotherapy drugRoy 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, identifies patients at high risk of biochemical failure.Intrinsic markers of tumour hypoxia

7、 and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort studyHIF-1 alpha score 4(B) HIF-1 alpha score 1(C) HIF-1 alpha score 0 Radiotherapy cohort.Radical prostatectomy cohortKourti, Int J

8、 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 Resistance

9、RelatedProtein 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醌類:如絲裂霉素C、E09 芳香族N-氧化物: TPZ 脂肪族N-氧化物:AQ4N 硝基雜環(huán)類:細(xì)胞毒劑CB1954、SN-3862 缺氧標(biāo)志物NITP、SR4554Inhibition of HIF-1a 拓?fù)洚悩?gòu)酶-1 抑制劑 微管靶向因子 信號轉(zhuǎn)導(dǎo)抑制劑 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