Transport proteins in drug resistance: detection and prognostic significance in acute myeloid leukemia.
Resistance to natural product-derived anti-cancer drugs, such as the anthracyclines and etoposide, contributes to the failure of chemotherapeutic treatment of leukaemia. One biological resistance mechanism of potential importance is the overexpression of the plasma membrane drug transporter proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP). Many studies have reported evidence for a correlation of Pgp/MDR1 expression with unfavourable prognostic features in acute myeloid leukaemia (AML). Failure to achieve complete remission (CR) is correlated with Pgp and the CD34+ phenotype. For MRP fewer data are available, which suggest a basal expression level in most AMLs. Another protein reported to correlate with treatment failure in AML is the lung resistance protein or major vault protein (LRP), a protein with a still unknown function. Co-expression of Pgp and LRP especially seems to define an adverse prognostic population. Further progress towards the understanding of the clinical importance of these proteins is hampered by the lack of validation of methods to determine their expression. A reliable way to measure Pgp seems to be the assessment of the active transport of fluorescent Pgp substrates, such as rhodamine 123 out of AML cells. Such functional Pgp assays can be used to validate mRNA or protein measurements and to quantify the effect of Pgp or the magnitude of the effect of a blocker of the Pgp-mediated drug efflux on the intracellular drug concentration. The prognostic value of such methods has still to be shown.
Broxterman
H J
HJ
Department of Medical Oncology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
Schuurhuis
G J
GJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D000208:Acute Disease; D003524:Cyclosporins / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D011379:Prognosis; D012261:Ribonucleoproteins / Q000187:drug effects / Q000378:metabolism; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003524:Cyclosporins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012261:Ribonucleoproteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C070272:valspodar