GENETIC ANALYSIS OF THE MULTIPLE DRUG RESISTANCE PHENOTYPE IN TUMOR CELLS

肿瘤细胞多重耐药表型的遗传分析

• 批准号: 4691877
• 负责人: M M GOTTESMAN
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4691877
• 关键词: colchicine; combination cancer therapy; combination chemotherapy; cytogenetics; doxorubicin; drug interactions; drug resistance; human tissue; linkage mapping; model design /development; molecular biology; monoclonal antibody; mutant; neoplasm /cancer genetics; pharmacokinetics; pleiotropism; puromycin; tissue /cell culture; vinblastine; vincristine

During the course of chemotherapy of human cancers, variants which are resistant to multiple drugs frequently arise. We have been investigation the genetic and biochemcial basis for this pleiotropic resistance of human tumor cells to chemotherapeutic agents. A model system using the cultured KB cell, a human carcinoma cell line, has been developed in which mutant cells selected independently for resistance to high levels of either colchicine, adriamycin or vinblastine have also been found to be cross-resistant to colchicine, adriamycin, vincristine, vinblastine, puromycin and actinomycin-D. Genetic linkage of these multiple drug resistances in the colchicine-selected line has been demonstrated by their coordiante appearance, coordinate reversion, codominance and cosegregation in somatic cell hybrids, and cotransfer by DNA-mediated gene transfer. Accumulation of several of the drugs involved in the multiple drug-resistance phenotype has been shown to be reduced in the KB cells. Drug-resistance correlates with the loss of a family of glycoproteins of molecular weights 70-80,000 on the cell surface detected by polyclonal and monoclonal antibodies and, in some cases, the appearance of a low molecular weight protein (p21). Drug-resistance also correlates with amplification of DNA segment detected either by an in gel renaturation technique or on Southern blots using probes cloned from amplified DNA in drug-resistant hamster cells.

在人类癌症的化疗过程中， 对多种药物的耐药性经常出现。 我们一直在调查 人类这种多效性抗性遗传和生物化学基础 肿瘤细胞与化疗剂的反应。 使用培养的 KB细胞，一种人癌细胞系，已经开发了其中突变的 独立选择的细胞对高水平的 还发现秋水仙碱、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。 这些多种药物的遗传连锁 秋水仙素选择系中的抗性已经通过它们的 共显性、共分离 在体细胞杂种中，以及通过DNA介导的基因转移的共转移。 多种药物的累积 已经显示KB细胞中的耐药性表型减少。 耐药性与一个糖蛋白家族的丧失有关， 通过多克隆检测细胞表面上的分子量为70- 80，000， 单克隆抗体，在某些情况下，出现低分子量 重量蛋白（p21）。 耐药性也与扩增有关 通过凝胶内复性技术或 使用从耐药细胞扩增DNA克隆的探针进行Southern印迹 仓鼠细胞