Abstract
Multilocus genotypes have been shown to be of relevance for using pharmacogenomic principles to individualize drug therapy. As it relates to thiopurine therapy, genetic polymorphisms of TPMT are strongly associated with the pharmacokinetics and clinical effects of thiopurines (mercaptopurine and azathioprine), influencing their toxicity and efficacy. We have recently demonstrated that TPMT and ITPA genotypes constitute a multilocus genotype of pharmacogenetic relevance for children with acute lymphoblastic leukemia (ALL) receiving thiopurine therapy. The use of high-throughput genomic analysis allows identification of additional candidate genetic factors associated with pharmacogenetic phenotypes, such as TPMT enzymatic activity: PACSIN2 polymorphisms have been identified by a genome-wide analysis, combining evaluation of polymorphisms and gene expression, as a significant determinant of TPMT activity in the HapMap CEU cell lines and the effects of PACSIN2 on TPMT activity and mercaptopurine induced adverse effects were confirmed in children with ALL. Combination of genetic factors of relevance for thiopurine metabolizing enzyme activity, based on the growing understanding of their association with drug metabolism and efficacy, is particularly promising for patients with pediatric ALL. The knowledge basis and clinical applications for multilocus genotypes of importance for therapy with mercaptopurine in pediatric ALL is discussed in the present review.
Highlights
The principle of personalized therapy is the identification and application of features associated with treatment response, to select adequate medications and their doses, in order to offer to patients the most effective treatment, with the lower incidence of adverse events (Cheok and Evans, 2006)
GENETIC FEATURES MAY INFLUENCE RESPONSE TO THERAPY Genetic polymorphisms for genes involved in drug metabolism, transport and molecular mechanism of action can alter the concentration of active metabolites and the molecular function of drugs’ targets and the efficacy and safety of pharmacological therapies (Paugh et al, 2011; Pinto et al, 2012)
TPMT AND inosine triphosphate pyrophosphatase (ITPA) AND MAINTENANCE THERAPY FOR PEDIATRIC acute lymphoblastic leukemia (ALL) In addition to TPMT, other genetic factors may alter the effects of mercaptopurine, their clinical importance has not been as well characterized
Summary
The principle of personalized therapy is the identification and application of features associated with treatment response, to select adequate medications and their doses, in order to offer to patients the most effective treatment, with the lower incidence of adverse events (Cheok and Evans, 2006). Pharmacological therapy for childhood ALL consists in protocols in which specific treatment approaches may differ but consistently comprise three major treatment phases: remission induction therapy followed by consolidation/intensification therapy and continuation/maintenance treatment to eliminate residual leukemic cells (Pui and Evans, 2006). The purine analog mercaptopurine is a key medication for the successful treatment of childhood ALL, in particular for the consolidation and continuation therapies and is used in combination with the folate analog methotrexate: for the success of ALL treatment, the 18–24 months of adequate maintenance therapy comprising mercaptopurine and methotrexate have a key role and are necessary to prolong and consolidate the remission obtained during the initial treatment phases (Pui and Evans, 2006; Paugh et al, 2010; Stocco et al, 2010)
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