Biology and modulation of multidrug resistance (MDR) in hematological malignancies.

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.