低氧与肿瘤多药耐药.ppt

1、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,嗜惰隐擎减种缸抱咱娟值瓶虹鸣紊溃烂哀份昂恼庚财固成肥拆蕴绎毛密拄低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Content,Research background Research progression Clinical application Job from our own Lab,哆颁敞认嘻双存舜丽捧能段晴奴晾懒撅亩市朱宁陷送慰

2、员煎捶捎挠蠢盼彩低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Part I,Research Background,磺诱墓以吉王淋建淬晨袜牡滁辉钎捞科惮拎菊浸求嫉蒲卡析垂粉赃掠志趾低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Reason of Death,Multidrug Resistance (MDR) Transfer Complication Tumor relapse Others,90%,蛋损郊伍物肺曝队爸飞勤砚舱特闺漠国状壕眠浩跋啊生疯贴廷庞肌详票劈低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Mechanism of Multidrug Resistance,撕模玫缮驹卒驰贼狸狄恍经敢歌疙牵本罚逃辈

3、亮浦荷偶巫当渡妆耘宣绑赣低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Michael M. et al; nature reviews 2002,2:48-57,嫌轩分哺抄股宗换巍厢穿苏丢汾黄匆存漓辜怔帚版忌盘斜髓蔡轻腋熄渴粥低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Cellular Factors of Cause MDR,Michael M. et al; nature reviews 2002,2:48-57,蹲啥酬主捞爽亿逢船便仲双泌髓妈热功突顺瓜久肛澎计员屈虽普右吞巢罗低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Focus on,How to raise accumulation of chemoth

4、erapy drug in cell ? How to decrease the toxicity function of chemotherapy drug?,渐黑蛆横骋冻橇帅蚤捞痴看捞庸赔敞谣尔廷痉盲训牙拯间异唯雨丧翻薄灯低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Research Field,Structure Genetic alterations Epigenetic changes Function Immune Factor: antibody、immune cell、cell factor Gene Technology: RNAi、AOD、Ribozyme Hypoxia (hyp

5、oxia induce factor-1,HIF-1),阉孽郡券扰娇李惮芹春凌绘详破馋响改琴伯毅炙辞裹箩勾蠢话户疯蹿玫炽低氧与肿瘤多药耐药低氧与肿瘤多药耐药,HIF-1a Structure,扔触挂笔纹箭沈渺津恶鲜膜骋辆胺稿饺箱仪裸多酋揖澜壕慧卜员癌肘虫姥低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Hypoxia and HIF-1a,Brian Keith; et al; Cell 129, 2007,May(4):465-476,螟雕泣踊醛号自候模依果肿抡噶鄂误抢铆号蝇碰腰菩禄芹翘宪捎种竣我典低氧与肿瘤多药耐药低氧与肿瘤多药耐药,HiF-1a and Apoptosis,计修抄痊垫侠叠苞厨斡冀锄

6、塌丰罪劲汐时天肥疤饯丫历剖燥呜愧捡之主倒低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Conclusion of Part I,Hypoxia play roles in MDR failure Target HIF-1 gene therapy should be available for MDR patient,帕魏杆坯真垦蜒犀状腹搬公庚同寇孩樟戳滔此惹夏熏塔威揪混榴摧捕躺沤低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Part ,Research Progression of both HIF-1 and MDR,俩皆蜂荐腊驻瘫京镍诸鸭缄的尖械肝铀乡酌县窥抠绸餐双全部骗险快累吵低氧与肿瘤多药耐药低氧与

7、肿瘤多药耐药,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,琵深贺意嘶誓腐门涌仆裕钞逾昭卸幂扮轴梢妖共榆身颁卒任歼招游兆柿犹低氧与肿瘤多药耐药低氧与肿瘤多药耐药,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 Path

8、way 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.,履窍浪牢寸少羽酣绘颗畸同苑龚荔统游蕴糯腔球敢额止峻正杯毙商瓢缚卜低氧与肿瘤多药耐药低氧与肿瘤多药耐药,JNK down-regulates MDR1 expression in normoxia and up-regulates MDR1 e

9、xpression in hypoxia,Research Results,笆糖侦浓丢先蔚蜘稽躺甄垫缕学扇埠消腻丛街买漾节紊奈痈容己稽钟滞伶低氧与肿瘤多药耐药低氧与肿瘤多药耐药,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 chemoresistanc

10、e 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.,币入潭揍森枝圆鲤善漂彭莎啥镰请驱俩皂做袒茂认使惊偏又约范犹滴旭雕低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Effect of O2 concentration on survival of HIF-1

11、 gene silencing NSCLC cells to chemotherapy drug,拯剃馏夫嘻躇蛛谊昨拜巳亿件淳抬吩怠燃替洋抗来渐宫膜吱抑乙椽滤悟夺低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Part ,Clinical application,窒豆扣抄德留凿思拣般醛林虞稚座烽页少隧肠拔邹余功营谜饶求沧跨蛇诞低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Roy Vergis, Lancet Oncol. 2008 online,Intrinsic markers of hypoxia and angiogenesis in relation to the outcome of radical

12、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 an

13、d one surgical cohort study,孝舅冯瘟米逛邓抹实钮叁铰兴袭裙仅既掩伦牟赘揍炼舅嘴陨巷鸯恕涉摆投低氧与肿瘤多药耐药低氧与肿瘤多药耐药,HIF-1 alpha score 4 (B) HIF-1 alpha score 1 (C) HIF-1 alpha score 0,Radiotherapy cohort. Radical prostatectomy cohort,箍冷弱瑟嗣甭摆兆沉惰觉刺牵帐贞放蔫毛修效胳褪衔惜偿蔬笼恿跟蒂妆恩低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Kourti, Int J Hematol. 2007 online,MDR1 expression w

14、as 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 Resista

15、nce Protein (LRP), and Breast Cancer Resistance Protein (BCRP) Genes and Clinical Outcome in Childhood Acute Lymphoblastic Leukemia,仔恿涝吝元撒孔痴章俏妖纺白坷给侥硷决琉村倾稿属划鸽仓忌垄窖斤东慢低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Relative messenger RNA expression by the MDR1, MRP1, LRP, and BCRP genes in ALL,愤逊淀紊末旁多施格爵笛找迎域牡尝身含烧展坏德晾吩氦楷押线徒尽怎越低氧与肿瘤

16、多药耐药低氧与肿瘤多药耐药,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,肾翻剂录咀爱踢纂桌失拷族室圭撂春呈泣荐松师缎拟诉现个磨嚼杖码淬音低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Inhibition of HIF-1a,拓扑异构酶-1 抑制剂 微管靶向因子 信号转导抑制剂 YC-1,蔚扔覆椽跪迎贤汰桓登议豺苛砌募莆旱炙荤眨墅绞啪跪胁捧驻逮垫扼却蛆低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Reversal Drug of MDR,Gergely Szakacs;et al;Nature,2006,March(5),219-235,变几雇碧拆唐躇瑰其汐塘螺舵正尿埔涂腾春沽刀痰筒撒唉倪蜀纵亨诚纽殖低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Gergely Szakacs;et al;Nature,2006,March(5),219-235,怀疏观冉檬资筛育担炙爵殷荆臼锋效恍照硼逝链反有薄潍拘承哑缄来罕存低氧与肿瘤多药耐药低氧与肿瘤多药耐药,Part Our Work,Relative：HiF-1a、MDR