《小细胞肺癌靶向治疗》课件.ppt

小细胞肺癌耐药机制及治疗新靶点 简介 SCLC约占肺癌的15%，是一种化疗敏感实体肿瘤，表现早期广泛转移，化疗是SCLC治疗的主要手段，但在过去的20年，尽管化疗进展，其生存期没有显著的提高。 LD中位生存期为12-20个月，生存期5年患者不足6%-12%。ED中位生存期为7-12个月，生存期2年患者不足5%,5年生存率仅为2%。 原发或获得性耐药是限制化疗效果的主要原因。 深入了解SCLC耐药及生物学特性对克服耐药及寻找新的治疗靶点有临床意义。 耐药机制 MDR ATP-binding cassette Pgp MRP1，MRP2，MRP3 BCRP（breast cancer resistance protein） RLIP76 DNA excision repair gene 核苷酸切除修复( nucleotide excision repair,NER) CG-NER(global genomic NER):ERCC1 TC-NER(trancription-coupled NER):BRCA1（breast cancer susceptibility gene 1） ECM AKT/mTOR BCL-2/BCL-xl ATP-binding cassette transporters 目前为止，证实人类至少存在48种ABC（ATP-binding cassette ）transporters ，分为7个亚家族。 其中Pgp，MRP1， MRP2，MRP3 ，在SCLC体外试验研究较多，提示在多种SCLC耐药细胞中表达升高，主要机制是通过ATP依赖性药物输出泵增加肿瘤细胞药物外运，降低细胞内药物浓度，表现细胞耐药。 BCRP （breast cancer resistance protein）近来研究发现与SCLC耐药相关。 Immunohistochemical Expression of MRP2 and Clinical Resistance to Platinum-based Chemotherapy in Small Cell Lung Cancer n=61 transbronchial biopsy (TBB) specimens immunohistochemical analysis P-gp, MRP1, MRP2, and p53 ANTICANCER RESEARCH 27: 4351-4358 (2007) Response to chemotherapy according to immunostaining. Response to chemotherapy according to immunostaining (CAVor platinum-based chemotherapy). Multiple logistic regression analysis for chemotherapy response  Factor Odds ratio (95% CI) In platinum-based chemotherapy the expression of P-gp and MRP2 correlated with chemoresistance. This finding suggest that the immunohistochemical expression of MRP2 may be a useful predictor in the clinical resistance to cisplatin. Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer n=130 tumor biopsy specimens immunohistochemical analysis P-gp, MRP1, MRP2, and BCRP 　　　　　　　 　　　　　　　Lung Cancer. 2008 Nov 24. Chemotherapeutic regiment Association between expression of ABC transporter and response to chemotherapy and survival * p 0.05. the present stud