De Isabella P, Capranico G, Zunino F
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Life Sci. 1991;48(23):2195-205. doi: 10.1016/0024-3205(91)90333-7.
The conventional laboratory approach to study the mechanisms of drug resistance has been the selection of drug-resistant cell lines by continuous exposure to cytotoxic agents. Such lines, which are selected for resistance to a single agent, frequently display cross-resistance to a number of cytotoxic agents that are unrelated in both structure and proposed mechanism of action. Multidrug-resistant cells display reduced drug accumulation, which is the result of overexpression of a surface glycoprotein (P170). Although resistance to multiple antitumor agents is a common clinical problem in the treatment of cancer, the precise role of the P-glycoprotein-mediated mechanism in human tumors remains to be established. Many alterations in multidrug-resistant cells selected in vitro have been identified. The concomitant expression of multiple phenotypic differences, which appear to be favored by continued and prolonged drug exposure, makes analysis of critical individual resistance pathways more difficult. However, multiple factors may also be involved in the development of clinical resistance. Recent studies have identified alterations in DNA topoisomerase II activity and function as an alternative mechanism that contributes to the multidrug-resistance phenomenon or is responsible for a different type of drug resistance. The precise nature of these changes remains unclear. Available evidence supports the view that expression of the enzyme is an important determinant of cell sensitivity to DNA topoisomerase poisons, but that other changes involved in regulation of enzyme function and/or in the cellular processing of drug-induced DNA damage may be critical in determining the differential pattern of cell response to antitumor agents.
研究耐药机制的传统实验室方法是通过持续暴露于细胞毒性药物来筛选耐药细胞系。这些针对单一药物耐药性筛选出的细胞系，常常对许多在结构和作用机制上均无关联的细胞毒性药物表现出交叉耐药性。多药耐药细胞表现出药物蓄积减少，这是表面糖蛋白（P170）过度表达的结果。尽管对多种抗肿瘤药物的耐药性是癌症治疗中常见的临床问题，但P - 糖蛋白介导的机制在人类肿瘤中的精确作用仍有待确定。在体外筛选出的多药耐药细胞中已发现许多改变。多种表型差异的同时表达似乎因持续和长期的药物暴露而更易出现，这使得对关键的个体耐药途径进行分析变得更加困难。然而，临床耐药的发生可能也涉及多种因素。最近的研究已确定DNA拓扑异构酶II活性和功能的改变是导致多药耐药现象的另一种机制，或与另一种类型的耐药性有关。这些变化的确切性质仍不清楚。现有证据支持这样的观点，即该酶的表达是细胞对DNA拓扑异构酶毒物敏感性的重要决定因素，但参与酶功能调节和/或药物诱导的DNA损伤细胞处理的其他变化，在决定细胞对抗肿瘤药物的不同反应模式方面可能至关重要。
