Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia.

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.

• Authors: Juan Eduardo Megias-Vericat, David Martinez-Cuadron, Maria Jose Herrero, Salvador F Alino, Jose Luis Poveda, Miguel Angel Sanz, Pau Montesinos
• Journal: Current drug metabolism (Curr Drug Metab) Vol. 19 Issue 1 Pg. 55-74 ( 2018) ISSN: 1875-5453 [Electronic] Netherlands
• PMID: 29090664 (Publication Type: Journal Article, Review, Systematic Review)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Anthracyclines
• Cytarabine

Topics

• Anthracyclines (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cytarabine (therapeutic use)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Pharmacogenetics (methods)
• Polymorphism, Genetic (genetics)