Clinical relevance of P-glycoprotein expression in haematological malignancies

Although, generally speaking, haematological malignancies are chemotherapy-responsive tumours and high remission induction rates are obtained, disease-related death is the rule rather than the exception. The appearance of cell populations, resistant to multidrug-based chemotherapy, constitutes the major problem to achieve cures in these patients. Advances in cell biology have partly contributed to the elucidation of different multidrug resistance (MDR) mechanisms, which enable cells to survive the cytotoxic effects of multiple chemotherapeutic agents. Of these resistance mechanisms, the one that is referred to as classical MDR is the most extensively studied, both in the laboratory as well as in patients, and here we will focus on its clinical relevance in haematological malignancies. The classical MDR phenotype is caused by enhanced cellular drug efflux due to increased activity of a membrane-bound glycoprotein (P-glycoprotein) drug pump, that can pump out anthracyclines, anthracenediones, vinca alkaloids and epipodophyllotoxins, thereby actively lowering the intracellular drug concentrations to sublethal levels. As soon as molecular probes for the detection of MDR cells became available, clinical studies were initiated to answer three main questions. Do human tumour cells express P-glycoprotein? If so, is the expression indicative of a bad prognosis, c.q. resistant disease? And last but not least, can we interfere with the P-glycoprotein drug pump in the patient? Clinical data indicate that classical MDR may be involved in the development of drug resistance, especially in some haematological malignancies, such as acute myelocytic leukaemia (AML), non-Hodgkin's lymphomas (NHL), and multiple myelomas (MM). In almost all types of haematological malignancies, either untreated or treated, elevated P-glycoprotein levels have been reported, ranging from low to high. However, the acquisition of clinical MDR associated with P-glycoprotein expression occurs only in those diseases (for example, AML and MM) that are heavily treated with MDR-related drugs, probably by selection of pre-existing P-glycoprotein-expressing malignant cells. Since P-glycoprotein is found to be expressed on the membrane of normal haemopoietic progenitor cells as well, it seems likely that P-glycoprotein-positive haematological tumours develop by malignant transformation of P-glycoprotein-expressing normal haemopoietic counterparts. Especially for AML, convincing data have been reported in the literature to show that P-glycoprotein expression at diagnosis is a bad prognostic factor that predicts refractoriness. Using in vitro model systems for classical MDR, a large number of agents have been identified that can circumvent P-glycoprotein-mediated drug resistance, the so-called resistance modifying agents (RMA). Subsequently, clinical phase I and II studies have been initiated which combine the use of MDR-related drugs in conjunction with RMAs. The overall conclusions from such studies in AML, NHL, and MM are that modulation of drug resistance by RMAs seems promising and that further evaluation in prospective, randomized phase III trials is warranted