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Multidrug resistance (MDR) genes in haematological malignancies

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Abstract

The emergence of drug resistant cells is one of the main obstacles for successful chemotherapeutic treatment of haematological malignancies. Most patients initially respond to chemotherapy at the time of first clinical admission, but often relapse and become refractory to further treatment not only to the drugs used in the first treatment but also to a variety of other drugs. Laboratory investigations have now provided a cellular basis for this clinical observation of multidrug resistance (MDR). Expression of a glycoprotein (referred to as P-glycoprotein) in the membrane of cells made resistantin vitro to naturally occurring anticancer agents like anthracyclines, Vinca alkaloids and epipodophyllotoxins, has been shown to be responsible for the so-called classical MDR phenotype. P-glycoprotein functions as an ATP-dependent, unidirectional drug efflux pump with a broad substrate specificity, that effectively maintains the intracellular cytotoxic drug concentrations under a non-cytotoxic threshold value. Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas. Since in model systems for P-glycoprotein-mediated MDR, drug resistance may be circumvented by the addition of non-cytotoxic agents that can inhibit the outward drug pump, clinical trials have been initiated to determine if such an approach will be feasible in a clinical situation. Preliminary results suggest that some haematological malignancies, among which are acute myelocytic leukaemia, multiple myeloma and non-Hodgkin's lymphoma, might benefit from the simultaneous administration of cytotoxic drugs and P-glycoprotein inhibitors. However, randomised clinical trials are needed to evaluate the use of such resistance modifiers in the clinic.

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Abbreviations

ALL:

acute lymphocytic leukaemia

AML:

acute myelocytic leukaemia

BM:

bone marrow

CAT:

chloramphenicol acetyltransferase

CLL:

chronic lymphocytic leukaemia

CML:

chronic myelocytic leukaemia

CR:

complete remission

HCL:

hairy cell leukaemia

MDR:

multidrug resistance

MDS:

myelodysplastic syndrome

MM:

multiple myeloma

MoAb:

monoclonal antibody

NHL:

non-Hodgkin's lymphoma

PB:

peripheral blood

PCR:

polymerase chain reaction

PLL:

prolymphocytic leukaemia

RMA:

resistance modifying agent

VAD:

vincristine, doxorubicin, dexamethasone

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  1. Department of Medical Oncology, Rotterdam Cancer Institute, P.O. Box 5201, 3008 AE, Rotterdam, The Netherlands

    K. Nooter

  2. Department of Haematology, University Hospital Dijkzigt, Rotterdam, The Netherlands

    P. Sonneveld

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  1. K. Nooter
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  2. P. Sonneveld
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Nooter, K., Sonneveld, P. Multidrug resistance (MDR) genes in haematological malignancies. Cytotechnology 12, 213–230 (1993). https://doi.org/10.1007/BF00744665

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