Hirose Masao
Division of Transfusion Medicine, Tokushima University School of Medicine, Japan.
Int J Hematol. 2002 Aug;76 Suppl 2:206-11. doi: 10.1007/BF03165119.
Drug resistance is one of the most significant impediments in the treatment of hematological malignancies. There have been a number of studies on the incidence of P-GP expression in tumor cells or tissues, where detectable level of P-GP has been found in all types of hematological malignancies. P-GP expression and significance in the patients varies widely between reported studies on patients with different ages and different disease types. Some of this validation can be accounted for by the threshold used to consider a sample positive for P-GP. However, mdr-1 is likely important in determining therapeutic outcome in patients with AML, NHL, and MM, although there is a suggestion of a different "behavior" between adult and childhood AML. In contrast, the significant prognostic association with expression of MRP and LRP is not consistent with disease types and disease stages. Clinical trials of modulation of MDR have been limited by following major factors. One is inability of achieving adequate blood levels of the modulator to reverse MDR, and the other is presence of other resistance mechanisms in addition to P-GP. The fact that P-GP modulators alter the pharmacokinetics of anti-cancer drugs can potentially increase toxicities if the dose of anticancer drugs is not appropriately reduced. Recently, MDR modulators such as valspodar have demonstrated substantial inhibition of P-GP. In this presentation, a number of characteristics in VCR-resistant cells are reported. We demonstrate that acquisition of MDR or recovery from MDR phenotypes differ in one cell type to another, a marked correlation between P-GP and susuceptibility to oxygen radicals, and altered gene expression of cell membrane antigen and apoptosis cascade genes. The efficacy of immunotherapies depends on the altered or unchanged target molecules of MDR cells. Thus, immunotherapies or reversal agents that aim at these substances in tumor cells should be useful to overcome MDR phenotypes.
耐药性是血液系统恶性肿瘤治疗中最显著的障碍之一。关于肿瘤细胞或组织中P -糖蛋白（P - GP）表达发生率的研究已有多项，在所有类型的血液系统恶性肿瘤中均发现了可检测水平的P - GP。不同年龄和不同疾病类型患者的报告研究中，P - GP在患者中的表达及意义差异很大。部分这种差异可归因于用于判定样本P - GP阳性的阈值。然而，多药耐药基因1（mdr - 1）在决定急性髓系白血病（AML）、非霍奇金淋巴瘤（NHL）和多发性骨髓瘤（MM）患者的治疗结果中可能很重要，尽管有迹象表明成人和儿童AML之间存在不同的“行为”。相比之下，多药耐药相关蛋白（MRP）和肺耐药相关蛋白（LRP）表达与预后的显著关联在不同疾病类型和疾病阶段并不一致。多药耐药（MDR）调节的临床试验受到以下主要因素的限制。一是无法使调节剂达到足够的血药浓度以逆转MDR，另一个是除P - GP外还存在其他耐药机制。如果抗癌药物剂量未适当降低，P - GP调节剂改变抗癌药物药代动力学这一事实可能会增加毒性。最近，诸如伐司朴达等MDR调节剂已显示出对P - GP的显著抑制作用。在本报告中，报道了长春新碱（VCR）耐药细胞的一些特征。我们证明，MDR的获得或从MDR表型的恢复在不同细胞类型之间存在差异，P - GP与对氧自由基的敏感性之间存在显著相关性，以及细胞膜抗原和凋亡级联基因的基因表达发生改变。免疫疗法的疗效取决于MDR细胞的靶分子是否改变。因此，针对肿瘤细胞中这些物质的免疫疗法或逆转剂应有助于克服MDR表型。
