GENETIC ANALYSIS OF THE MULTIPLE DRUG RESISTANCE PHENOTYPE IN TUMOR CELLS

对多种药物的耐药性是治疗的主要障碍。 人类癌症的成功化疗。 探讨 这种多药耐药（MDR）的遗传和生化基础 表型，我们已经开发了一个模型系统，使用培养的KB 细胞，独立选择的人癌细胞系， 对高水平秋水仙碱、阿霉素或 长春碱对秋水仙碱，阿霉素， 长春新碱、长春碱、嘌呤霉素和放线菌素D。 这 耐药性是由MDR 1基因的表达引起的，该基因编码 一种170，000道尔顿的膜糖蛋白（P-糖蛋白）， 一种多药物转运蛋白。 ATP依赖的转运 长春碱已经使用来自MDR的膜囊泡被证实， 细胞 其中克隆了MDR 1 cDNA的表达载体 赋予药物敏感细胞完整的莫尔表型， 携带MDR 1基因的逆转录病毒。 MDR 1 RNA的表达和 P-糖蛋白存在于正常的肾脏、肝脏、结肠和肾上腺中 在这些组织衍生的肿瘤中， 对化疗和其他几种肿瘤都有抗药性。 儿童白血病、神经母细胞瘤、 横纹肌肉瘤和嗜铬细胞瘤可能与 增加MDR 1 RNA水平。

Resistance to multiple drugs is a major impediment to the successful chemotherapy of human cancers. To investigate the genetic and biochemical basis for this multidrug resistance (MDR) phenotype, we have developed a model system using the cultured KB cell, a human carcinoma cell line selected independently for resistance to high levels of either colchicine, adriamycin or vinblastine which is cross-resistant to colchicine, adriamycin, vincristine, vinblastine, puromycin, and actinomycin D. This resistance results from expression of the MDR1 gene which encodes a 170,000 dalton membrane glycoprotein (P-glycoprotein) which is a multidrug transport protein. ATP-dependent transport of vinblastine has been demonstrated using membrane vesicles from MDR cells. Expression vectors into which the MDR1 cDNA are cloned confer the complete MOR phenotype on drug-sensitive cells, as does a retrovirus carrying the MDR1 gene. Expression of MDR1 RNA and P-glycoprotein occurs in normal kidney, liver, colon, and adrenal and in tumors derived from these tissues which are intrinsically resistant to chemotherapy as well as several other tumors. Acquired drug-resistance in childhood leukemia, neuroblastoma, rhabdomyosarcoma and in pheochromocytoma may be associated with increased MDR1 RNA levels.