The prognostic significance of membrane transport-associated multidrug resistance (MDR) proteins in leukemia.
A major problem in the treatment of leukemia is the development of resistance to chemotherapeutic agents. There are several ways for cancer cells to develop resistance or defense mechanisms against cytotoxic drugs. This review paper will focus on membrane transport-associated multidrug resistance (MDR). The proteins involved, P-glycoprotein (P-gp), MRP1 and LRP/MVP, share the ability to act as drug transport proteins. Following upregulation of the mdr-1 gene, the energy-dependent transmembrane P-gp overexpression results in diminished intracellular concentrations of anthracyclins, vinca-alkaloids and epipodophyllotoxins. The other transmembrane protein, MRP1, also has intracellular epitopes which are involved in intracellular redistribution and sequestration of drugs. The last named mechanism has also been ascribed to LRP, a protein which only occurs intracellularly. In leukemia patients, cellular drug resistance profiles determined in vitro at the time of presentation show a strong correlation with outcome. In AML, mdr-1 overexpression at diagnosis is a strong independent predictor for CR and long-term survival. In ALL, mdr-1 expression is of minor importance for prediction of outcome. In AML, MRP1 expression at diagnosis is not correlated with clinical response and survival in most studies. In ALL, MRP1 expression at diagnosis is not associated with response and long-term survival in the few studies on this aspect which have been published. The studies on LRP in AML emphasize the importance of the correlation between LRP-expression and anthracycline accumulation and suggest that LRP-expression has prognostic value at diagnosis. However, there is an equal number of studies where a predictive value in the case of LRP-expression in de novo AML cannot be shown. The highest levels of LRP have been reported in multiple relapses of ALL. Furthermore, new membrane-associated drug transport proteins have been reported including the transporter associated with antigen processing (TAP), the anthracyclin resistance-associated protein (ARA), five new homologues of MRP (MRP2, or MOAT, MRP3, MRP4, MRP5, and MRP6), the sister of P-glycoprotein (sP-gp) and breast cancer resistance protein (BCRP). Studies on the (clinical) significance of these proteins have not yet been reported.
van den Heuvel-Eibrink
M M
MM
Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Rotterdam, The Netherlands.
Sonneveld
P
P
Pieters
R
R
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D015703:Antigens, CD / Q000502:physiology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001692:Biological Transport / Q000235:genetics; D002462:Cell Membrane / Q000502:physiology; D002648:Child; D018432:Drug Resistance, Multiple / Q000235:genetics* / Q000502:physiology; D019450:Genes, MDR / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D011379:Prognosis; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D015703:Antigens, CD; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1