对用高浓度甲氨蝶呤筛选的人白血病细胞中不典型多药耐药性的表型和细胞遗传学分析。

Phenotypic and cytogenetic analysis of atypical multidrug resistance in human leukaemic cells selected with methotrexate at high concentration.

作者信息

Kavallaris M, Haber M, Norris M D, Pittman S M, Reed C, Stewart B W

机构信息

Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, Randwick, Sydney, N.S.W., Australia.

出版信息

Cancer Lett. 1990 Jun 15;51(3):193-201. doi: 10.1016/0304-3835(90)90102-4.

DOI:10.1016/0304-3835(90)90102-4

PMID:1972035

Abstract

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype. The mechanism(s) underlying resistance to vincristine, vinblastine and actinomycin D in the most resistant subline (CEM/MTX R3) has now been investigated. Efflux of [3H]vincristine was more rapid in CEM/MTX R3 than in either CCRF-CEM cells or a methotrexate-resistant subline not refractory to Vinca alkaloids. In addition, verapamil completely reversed resistance to vincristine, vinblastine and actinomycin D in the CEM/MTX R3 cells. While these results are suggestive of P-glycoprotein-mediated multidrug resistance, Northern analysis revealed no detectable expression of the mdr 1/gene in CEM/MTX R3 cells. Likewise, karyotypic analysis of the resistant subline, while revealing certain clonal abnormalities, provided no evidence of alteration in the mdr 1/gene locus on chromosome 7. The data suggest therefore the operation, in these cells, of a novel mechanism of resistance.

摘要

先前已证明，一系列经筛选对甲氨蝶呤具有极强抗性的CCRF - CEM亚系，对多种属于多药耐药表型的药物表现出交叉抗性。现已对最具抗性的亚系（CEM/MTX R3）中对长春新碱、长春花碱和放线菌素D的耐药机制进行了研究。在CEM/MTX R3中，[3H]长春新碱的外排比CCRF - CEM细胞或对长春花生物碱不耐药的甲氨蝶呤耐药亚系更快。此外，维拉帕米完全逆转了CEM/MTX R3细胞对长春新碱、长春花碱和放线菌素D的耐药性。虽然这些结果提示存在P - 糖蛋白介导的多药耐药性，但Northern分析显示在CEM/MTX R3细胞中未检测到mdr 1/基因的表达。同样，对耐药亚系的核型分析虽然揭示了某些克隆异常，但未提供7号染色体上mdr 1/基因位点发生改变的证据。因此，数据表明在这些细胞中存在一种新的耐药机制。