Reversal of drug resistance in a human colon cancer xenograft expressing MDR1 complementary DNA by in vivo administration of MRK-16 monoclonal antibody.
Reversal of drug resistance in a human colon cancer xenograft expressing MDR1 complementary DNA by in vivo administration of MRK-16 monoclonal antibody.
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通过体内施用 MRK-16 单克隆抗体逆转表达 MDR1 互补 DNA 的人结肠癌异种移植物的耐药性。
DOI：
10.1093/jnci/83.19.1386
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Tsuruo,T
中科院分区：
文献类型：
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作者：
Pearson,JW;Fogler,WE;Volker,K;Usui,N;Goldenberg,SK;Gruys,E;Riggs,CW;Komschlies,K;Wiltrout,RH;Tsuruo,T
克服瘤形成中的多药耐药性的一种策略是抑制gp 170糖蛋白（相对分子量，170 000），其充当质膜、能量依赖性、药物-效应通量泵。人结肠癌细胞系HT-29在无胸腺NCr-nu/nu裸小鼠中作为腹水瘤生长，通过用MDR 1（也称为PGY 1）逆转录病毒感染而产生多药耐药性。被称为HT-29 mdr 1，它被用于研究通过抗P-糖蛋白单克隆抗体MRK-16在体内逆转耐药性。流式细胞术和放射免疫测定表明，与其对未感染的亲代细胞系（HT-29 pa）的反应性相比，MRK-16对HT-29 mdr 1细胞的反应性显着增加。长春新碱对HT-29 pa和HT-29 mdr 1细胞的50%抑制浓度（IC 50）分别为2.5和15 ng/mL。MRK-16单克隆抗体不影响HT-29细胞对长春新碱的敏感性。在组织培养中用10 μg/mL MRK-16预处理HT-29 mdr 1细胞可部分恢复长春新碱敏感性（IC 50 = 7 ng/mL）。然后在体内检测MRK-16对长春新碱敏感性的调节。经腹腔移植5 × 106 HT-29或HT-29 mdr 1的小鼠中位生存期分别为37和39天。从肿瘤注射后10天开始，每周用1 mg/kg长春新碱治疗小鼠3周，导致HT-29荷瘤小鼠的中位生存时间显著增加（68天，P. <.0001），但对HT-29 mdr 1荷瘤小鼠无明显作用。然而，在长春新碱治疗前用MRK-16治疗HT-29 mdr 1肿瘤小鼠，逆转了对药物的耐药性（中位生存时间= 64天，P<0.0001）。单独使用MRK-16单克隆抗体对注射HT-29 paror HT-29 mdr 1细胞的小鼠的中位生存时间没有影响。这些结果表明，采用针对gp 170的单克隆抗体的策略可能在临床上用于逆转多药耐药性。[J Natl Cancer Inst 83：1386-1391，1991]
One strategy to overcome multidrug resistance in neoplasia is to inhibit the gpl7O glycoprotein (relative molecular mass, 170 000) that functions as a plasma membrane, energy-dependent, drug-ef flux pump. The human colon cancer cell line HT-29, which grows as an as citic tumor in athymic NCr-nu/nu nude mice, was made multidrug resistant by infection with an MDR1 (also known as PGY1) retrovirus. Referred to as HT-29mdr1, it was used to study reversal of drug resistance in vivo by the anti-P-glycoprotein monoclonal antibody MRK-16. Flow cytometry and radioimmunoassay demonstrated a marked increase in MRK-16 reactivity on HT-29mdr1cells as compared with its reactivity on the parental, uninfected cell line (HT-29parThe 50% in hibitory concentrations (IC50) of vincristine on HT-29parand HT-29mdr1cells were 2.5 and 15 ng/niL, respectively. The MRK-16 monoclonal antibody did not affect the vincristine sensitivity of the HT-29parcells. Pretreatment of HT-29mdr1cells with 10 μg/mL MRK-16 in tissue culture partially restored the vincristine sensitivity (IC50= 7 ng/mL). This modulation of vincristine sensitivity by MRK-16 was then tested in vivo. The median survival times of mice given in traperitoneal transplants of 5 × 106HT-29paror HT-29mdr1were 37 and 39 days, respectively. Treatment of mice with 1 mg/kg vincristine weekly for 3 weeks, beginning 10 days after tumor injection, resulted in a significant increase in the median survival time of the HT-29partumor-bearing mice (68 days, P.<.0001) but it had no effect on the HT-29mdr1tumor-bearing mice. However, treatment of mice bearing the HT-29mdr1tumor with MRK-16 before vincristine therapy reversed the resistance to the drug (median survival time = 64 days, P<.0001) The MRK-16 monoclonal antibody alone had no effect on the median survival time of mice given an injection of either HT-29paror HT-29mdr1cells. These results suggest that strategies employing monoclonal antibody against gpl70 may be clinically useful to reverse multidrug resistance. [J Natl Cancer Inst 83:1386–1391, 1991]