EMERGENCE OF ADRIAMYCIN RESISTANCE IN LEUKEMIA CELLS

许多不同癌症的成功治疗正被严重限制在 对化疗药物的抗药性。大多数关于耐药性的研究都有 检查了高度耐药的细胞系，这些细胞系通常显示出一种多药 耐药(MDR)表型。低水平抗性突变体也出现在 临床背景下，正如体外研究表明的那样，它们可能先于突变 表现出高水平的抗性。这些研究建议研究一系列 越来越多的阿霉素耐药小鼠白血病细胞系 这个实验室。突变体表现出不同程度的抗药性 阿霉素，对长春新碱和长春新碱有/无伴随耐药性 依托泊苷。变态药物蓄积的作用及其机制基础 将对抵抗的贡献者进行评估。特征化和 多药耐药细胞系PC4-1相关蛋白的鉴定 40在不过度表达P-糖蛋白的情况下外流柔红霉素将 进行手术并克隆该基因。这项研究的目的是确定 早、中水平抗性植株的转运减少 变种人。了解早期突变体的抗药性基础， 出现在接近临床的药物水平和暴露水平 情况，可能会提出新的方法来控制新的 抗性及其向更高水平和交叉抗性的进展 表型。

Successful therapy of many different cancers is being severely curtailed by resistance to chemotherapeutic agents. Most studies of resistance have examined highly resistant cell lines which often show a multidrug resistance (MDR) phenotype. Low level resistant mutants also appear in the clinical setting and they may, as in vitro studies suggest, precede mutants expressing high level resistance. These studies propose to study a series of increasingly adriamycin resistant murine leukemia cell lines derived in this laboratory. Mutants appear with different levels of resistance to adriamycin, with/without concomitant resistance to vincristine and etoposide. The role and mechanistic basis of altered drug accumulation as a contributor to resistance will be assessed. Characterization and identification of the protein involved in the multiresistant cell line PC4- 40 which effluxes daunorubicin without over-expressing P-glycoprotein will be performed and the gene cloned. This research aims to define the role of decreased transport in resistance of early to intermediate level resistant mutants. Understanding the basis for resistance in the early mutants, which appear at levels and exposures of drug close to the clinical situation, may suggest new approaches to controlling the emergence of resistance as well as its progression to higher levels and cross-resistance phenotypes.