低氧與腫瘤多藥耐藥ppt課件

1、低氧與腫瘤多藥耐藥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 1;.2ContentResearch backgroundResearch progressionClinical applicationJob from our own Lab3Part IResearch Background4Reason of Deathu Multidrug Resistance (MD

2、R)u Transfer u Complication u Tumor relapseu Others90%5Mechanism of Multidrug Resistance6 Michael M. et al; nature reviews 2002,2:48-577Cellular Factors of Cause MDR Michael M. et al; nature reviews 2002,2:48-578Focus onHow to raise accumulation of chemotherapy drug in cell ?How to decrease the toxi

3、city function of chemotherapy drug?9Research 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) 10HIF-1a a Structure11Hypoxia and HIF-1a aBrian Keith; et al; Cel

4、l 129, 2007,May(4):465-47612HiF-1a a and Apoptosis13Conclusion of Part IHypoxia play roles in MDR failureTarget HIF-1 gene therapy should be available for MDR patient 14Part Research Progression of both HIF-1 and MDR15丁震宇丁震宇,梁后杰梁后杰 免疫學(xué)雜志免疫學(xué)雜志 2008HIF-1a與P-gp 在結(jié)腸癌組織表達(dá)存在相關(guān)性兩者相互作用共同參與結(jié)腸癌多藥耐藥的發(fā)生HIF-1a a

5、與與P-gp 在結(jié)腸癌組織中的表達(dá)及意義在結(jié)腸癌組織中的表達(dá)及意義16Min 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 express

6、ion in normoxia. up-regulation of MDR1 expression in hypoxia.17JNK down-regulates MDR1 expression in normoxia and up-regulates MDR1 expression in hypoxiaResearch Results18Xianrang, et al Cancer Chemother Pharmacol,2006 online Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell

7、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.19Effect of O2 conc

8、entration on survival of HIF-1 gene silencing NSCLC cells to chemotherapy drug20Part Clinical application21Roy 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, identifi

9、es 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 study22HIF-1 alpha score 4(B) HIF-1 alpha score 1

10、(C) HIF-1 alpha score 0 Radiotherapy cohort.Radical prostatectomy cohort23Kourti, 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 ris

11、k 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 Leukemia24Relative messenger RNA expression by the MDR1

12、, MRP1, LRP, and BCRP genes in ALL25Activate Drug of Hypoxia醌類醌類:如絲裂霉素如絲裂霉素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 硝基雜環(huán)類硝基雜環(huán)類:細(xì)胞毒劑細(xì)胞毒劑CB1954、SN-3862 缺氧標(biāo)志物缺氧標(biāo)志物NITP、SR455426Inhibition of HIF-1a u 拓?fù)洚悩?gòu)酶拓?fù)洚悩?gòu)酶-1 抑制劑抑制劑u 微管靶向因子微管靶向因子u 信號(hào)轉(zhuǎn)導(dǎo)抑制劑信號(hào)轉(zhuǎn)導(dǎo)抑制劑u YC-127Reversal Drug of MDRGergely Szakacs;et al;Nature,2006,March(5),219-23528Gergely Szakacs;et al;Nature,2006,March(5),219-23529Pa