Pgp and FLT3: identification and modulation of two proteins that lead to chemotherapy resistance in acute myeloid leukemia.
Acute myeloid leukaemia (AML) comprises 80% of acute adult leukaemias and the disease has mostly an unfavourable outcome. Diagnostic criteria rely primarily on morphological classification, while prognostic evaluation is determined by cytogenetic methods. Survival is highly variable and it is a matter of debate, whether alternative therapeutic approaches may improve the effectiveness of conventional cytotoxic drug treatment. Two transmembrane proteins undoubtedly contribute to worse prognosis: P-glycoprotein (Pgp) and FLT3. Pgp is a transmembrane, ATP-cassette binding efflux pump that efficiently removes structurally unrelated xenobiotics from leukaemic blasts. This leads to inefficiency towards several cytotoxic drugs, hence the phenomenon is called multidrug resistance. FLT3 is a transmembrane tyrosine kinase and an internal tandem duplication can considerably augment its kinase activity. Both mechanisms lead to chemotherapy resistance and significantly shorter survival; thus several studies have been designed to treat patients via therapeutic measures that neutralize these proteins. This review focuses on the pathophysiological phenomena and the detection methods of Pgp and FLT3 as well as on novel therapeutic strategies that are offered by their inhibition.
Kappelmayer
János
J
Department of Clinical Biochemistry and Molecular Pathology, Medical and Health Science Center, University of Debrecen, Hungary. kappelmayer@jaguar.unideb.hu
Udvardy
Miklós
M
Antal-Szalmás
Péter
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000502:physiology*; D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3