阿帕替尼治疗晚期胃癌病例分享课件.ppt

ABCB1 ABCC1 ABCG2 多个TKI抑制剂是ABC的底物 伊马替尼是ABCB1底物 吉非替尼、厄洛替尼、凡德他尼、拉帕替尼也显示抑制ABCB1和ABCG2的功能 阿帕替尼？ 在药物选择性细胞株中，阿帕替尼在逆转ABCB1和ABCG2介导的多药耐药的效果 在转染细胞株中，阿帕替尼在逆转ABCB1和ABCG2介导的多药耐药的效果 阿帕替尼可以明显增加过表达ABCB1或ABCG2的肿瘤细胞对其为ABCB1或ABCG2底物的抗肿瘤药物的敏感性 阿帕替尼显著增加DOX和Rho123在ABCB1和ABCG2过表达细胞中的蓄积 在多药耐药细胞中，阿帕替尼显著抑制ABCB1-和ABCG2介导的转运 阿帕替尼可以抑制细胞内DOX外排 ABCB1 ABCG2 阿帕替尼可以刺激ABCB1和ABCG2的ATP酶活性 阿帕替尼可以抑制用[125I]IAAP标记的ABCB1和ABCG2光亲和力 阿帕替尼没有明显改变ABCB1和ABCG2的mRNA或蛋白表达水平 阿帕替尼对多药耐药的逆转最可能是直接抑制ABCB1和ABCG2的外排功能 阿帕替尼可以逆转在裸鼠移植物模型中的ABCB1介导的多药耐药 阿帕替尼可以通过抑制ABC转运体的外排功能逆转多药耐药 患者接受的治疗 继续“阿帕替尼850mg qd”靶向治疗 POF方案化疗5周期（2015.08.14-2015.11.18） L-CF 0.3+5-FU 4.0+Tax210mg+OXA140mg 结果： 触诊腹壁结节明显缩小, 2015.10.26 MR示腹膜转移与前相仿，腹壁肿块1.7cm（PR, 2015.8.11: 2.9cm ） ECOG PS 0分 CEA ↓ 8.10 9.7 10.8 10.26 CEA(ng／ml) 6.8 7.1 5.3 4.3 * 2015.10.26 2015.8.11 阿帕替尼 + POF 思考 逆转耐药？ 联合使用？ 跨线？ * 患者的选择 2015.11.17 * * * The most common cause of MDR results from the overexpression of cell membrane–bound ATP-binding cassette (ABC) transporters, which actively extrude a variety of chemotherapeutic drugs out of the cancer cells, thereby attenuating their cytotoxic actions (2). Forty-eight ABC proteins have been identified in the human genome and are divided into seven subfamilies (A–G) based on sequence similarities (3). The ABC transporter subfamily B member ABC transporter subfamily B member 1 (ABCB1/MDR1/P-glycoprotein), subfamily C member 1 (ABCC1/MRP1), and subfamily G member 2 (ABCG2/BCRP) * Interestingly, several TKIs were found to interact with the major MDR transporters, such as ABCB1, ABCC1, and ABCG2. Initially, * Based on the cytotoxicity curves, apatinib was used at a maximum concentration of 3.0 μmol/L, a concentration at which more than 90% of the cells were viable in all cell lines used in the MDR reversal study IC50 (half maximal inhibitory concentration)是指被测量的拮抗剂的半抑制浓度。它能指示某一药物或者物质(抑制剂)在抑制某些生物程序(或者是包含在此程序中的某些物质，比如酶，细胞受体或是微生物)的半量 * 3 μmol/L apatinib completely reversed ABCG2-mediated resistance to mitoxantrone and SN