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 Content Research background Research progression Clinical application Job from our own Lab Part I Research Background Reason of Death u Multidrug Resistance (MDR) u Transfer u Complication u Tumor relapse u Others 90% Mechanism of Multidrug Resistance Michael M. et al; nature reviews 2002,2:48-57 Cellular Factors of Cause MDR Michael M. et al; nature reviews 2002,2:48-57 Focus on How to raise accumulation of chemotherapy drug in cell ? How to decrease the toxicity function of chemotherapy drug? Research Field u 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 Structure Hypoxia and HIF-1a Brian Keith; et al; Cell 129, 2007,May(4):465-476 HiF-1a and Apoptosis Conclusion of Part I Hypoxia play roles in MDR failure Target HIF-1 gene therapy should be available for MDR patient Part Research Progression of both HIF-1 and MDR 丁震宇 ,梁后杰 免疫学杂志 2008 HIF-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与 P-gp 在结肠癌组织中的表达及意义 Min Liu, et al, JBC,2007 online PO2-dependent differential regulation of multi-drug resistance 1 gene expression by the c-Jun NH2-terminal Kinase Pathway The 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 hypoxia Research Results Xianrang, 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 gene Hypoxia-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 drug Part Clinical application Roy Vergis, Lancet Oncol. 2008 online Intrinsic 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 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 cohort Kourti, 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 failure Expression of Multidrug Resistance 1 (MDR1), Multidrug ResistanceRelated Protein 1 (MRP1), Lung Resistance Protein (LRP), and Breast Cancer Resistance Protein (BCRP) Genes and Clinical Outcome in Childhood Acute Lymphoblastic Leukemia Relative messenger RNA expression by the MDR1, MRP1, LRP, and BCRP genes in ALL Activate Drug of Hypoxia 醌类 :如丝裂霉素 C、 E09 芳香族 N-氧化物 : TPZ 脂肪族 N-氧化物 :AQ4N 硝基杂环类 :细胞毒剂 CB1954、 SN-3862 缺氧标志物 NITP、 SR4554 Inhibition of HIF-1a u 拓扑异构酶 -1 抑制剂 u 微管靶向因子 u 信号转导抑制剂 u YC-1 Reversal Drug of MDR Gergely Szakacs;et al;Nature,2006,March(5),219-235 Gergely Szakacs;et al;Nature,2006,March(5),219-235 Part Our Wo