Title:Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia
Volume: 19
Issue: 1
Author(s): Juan Eduardo Megias-Vericat*, David Martinez-Cuadron, Maria Jose Herrero, Salvador F. Alino, Jose Luis Poveda, Miguel Angel Sanz and Pau Montesinos
Affiliation:
- Unidad de Farmacogenetica, Instituto Investigacion Sanitaria La Fe and Area del Medicamento, Hospital Universitario y Politecnico La Fe. Avda. Fernando Abril Martorell 106, 46026 - Valencia,Spain
Keywords:
Anthracyclines, idarubicin, daunorubicin, polymorphism, acute myeloid leukemia, metabolism, SNP.
Abstract: Background: Anthracyclines in combination with cytarabine have been the standard therapy for acute
myeloid leukemia (AML) for decades with high efficacy. However, the majority of patients will show initial resistance
or will relapse after initial complete remission. Genetic variability in genes involved in anthracyclines metabolic
pathway could be one of the causes of the interindividual differences in clinical outcomes.
Methods: A systematic review of published studies in AML cohorts was carried out in order to analyze the influence
of polymorphisms in genes of anthracycline metabolism on efficacy and toxicity.
Results: Polymorphisms in the main enzymes of anthracyclines metabolism (CBR, AKR, NQO1, NOS3) have been
related to lower enzymatic activity and higher cardiotoxicity. Moreover, variant alleles in the genes of carcinogens
and chemotherapy neutralizing enzymes (GST, SULT, NADP(H) oxidase) have been associated with ROS generation
and drug efficacy, influencing the survival rates and cardiac toxicities. In addition, genetic variability in the
transporters of anthracyclines could affect the intake in cells, including influx (SLC28A3, SLC22A12, SLCO1B1)
and efflux transporters (ABCB1, ABCC1, ABCC3, ABCG2).
Conclusion: The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences
observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical
practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the
toxicities.
