Baines P, Cumber P, Padua R A
Department of Haematology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Baillieres Clin Haematol. 1992 Oct;5(4):943-60. doi: 10.1016/s0950-3536(11)80053-3.
Multidrug resistance hampers successful chemotherapy in many haematological neoplasms and is mediated by several cellular proteins. In some cases, the genes encoding these proteins have been shown to confer resistance on transfer to drug-sensitive cell lines. This is true for the efflux pump product of the MDR1 gene, P-170. Upregulation of enzymes such as GST has been observed, although the contribution of this enzyme in drug resistance expressed by malignant haematopoietic cells is still uncertain. Cells also appear to be able to downregulate enzymes which are drug targets. Examples include the decrease in Topo II which accompanies the resistance shown by cells to VP-16 and VM-26. Although many reports include both presentation and relapsed patients, there are few data on samples drawn from the same patients before and after chemotherapy. While P-170 and GST appear to be raised more often in cells from resistant and relapsed disease, it is quite clear that such mechanisms can be active in de novo malignancy and do not necessarily emerge as a consequence of prior chemotherapy. Methods of detecting drug resistance are reviewed here; these include in vitro cellular assays for drug toxicity, and molecular, immunological and functional detection of P-170 or Topo II. The clinical evaluation of such assays is only just beginning and some of the data are contradictory. To some extent, this may reflect the complex way in which the various resistance mechanisms may interact. Nevertheless, there are some encouraging early signs that the application of these assays to clinical material will yield valuable data on the relative contributions of these mechanisms and on ways in which they may be overcome. At present, much attention has focused on the potential of agents which prevent the P-170 efflux pump from exporting cytotoxics from the cell. This is likely to be only the first of new therapies arising from an improved understanding of multidrug resistance. More immediately, assays for multidrug resistance and its parameters may find their place as routine diagnostic and prognostic tools in the laboratory.
多药耐药性阻碍了许多血液系统肿瘤化疗的成功，它由多种细胞蛋白介导。在某些情况下，编码这些蛋白的基因已被证明在转移至药物敏感细胞系时会赋予耐药性。MDR1基因的外排泵产物P-170就是如此。已观察到诸如谷胱甘肽S-转移酶（GST）等酶的上调，尽管这种酶在恶性造血细胞表达的耐药性中的作用仍不确定。细胞似乎也能够下调作为药物靶点的酶。例如，细胞对依托泊苷（VP-16）和替尼泊苷（VM-26）产生耐药性时，拓扑异构酶II（Topo II）会减少。虽然许多报告涵盖了初治和复发患者，但关于同一患者化疗前后样本的数据却很少。虽然P-170和GST似乎在耐药和复发疾病的细胞中更常升高，但很明显，这些机制在原发性恶性肿瘤中也可能起作用，不一定是先前化疗的结果。本文综述了检测耐药性的方法；这些方法包括体外细胞药物毒性测定，以及对P-170或Topo II的分子、免疫和功能检测。此类检测的临床评估才刚刚开始，一些数据相互矛盾。在某种程度上，这可能反映了各种耐药机制相互作用的复杂方式。然而，有一些令人鼓舞的早期迹象表明，将这些检测应用于临床材料将产生关于这些机制的相对贡献以及克服它们的方法的有价值数据。目前，很多注意力集中在能够阻止P-170外排泵将细胞毒性药物排出细胞的药物的潜力上。这可能只是因对多药耐药性有了更好理解而产生的新疗法中的第一种。更直接的是，多药耐药性及其参数的检测可能会在实验室中作为常规诊断和预后工具找到用武之地。
