Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia.
Pharmacogenetics covers the genetic variation affecting pharmacokinetics and pharmacodynamics, and their influence on drug-response phenotypes. The genetic variation includes an estimated 15 million single nucleotide polymorphisms (SNPs) and is a key determinator for the interindividual differences in treatment resistance and toxic side effects. As most childhood acute lymphoblastic leukemia treatment protocols include up to 13 different chemotherapeutic agents, the impact of individual SNPs has been difficult to evaluate. So far focus has mainly been on the widely used glucocorticosteroids, methotrexate, and thiopurines, or on metabolic pathways and transport mechanisms that are common to several drugs, such as the glutathione S-transferases. However, beyond the thiopurine methyltransferase polymorphisms, the candidate-gene approach has not established clear associations between polymorphisms and treatment response. In the future, high-throughput, low-cost, genetic platforms will allow screening of hundreds or thousands of targeted SNPs to give a combined gene-dosage effect (=individual SNP risk profile), which may allow pharmacogenetic-based individualization of treatment.
Davidsen
Marie Louise
ML
Pediatric Clinic II, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
Dalhoff
Kim
K
Schmiegelow
Kjeld
K
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins