Davidsen Marie Louise, Dalhoff Kim, Schmiegelow Kjeld
Pediatric Clinic II, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
J Pediatr Hematol Oncol. 2008 Nov;30(11):831-49. doi: 10.1097/MPH.0b013e3181868570.
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.
药物遗传学涵盖影响药物代谢动力学和药效动力学的基因变异，以及它们对药物反应表型的影响。这种基因变异包括估计达1500万个单核苷酸多态性（SNP），是个体间治疗抵抗和毒副作用差异的关键决定因素。由于大多数儿童急性淋巴细胞白血病治疗方案包含多达13种不同的化疗药物，单个SNP的影响难以评估。到目前为止，主要关注的是广泛使用的糖皮质激素、甲氨蝶呤和硫嘌呤，或者几种药物共有的代谢途径和转运机制，如谷胱甘肽S-转移酶。然而，除了硫嘌呤甲基转移酶多态性外，候选基因方法尚未在多态性与治疗反应之间建立明确的关联。未来，高通量、低成本的基因平台将能够筛选数百或数千个靶向SNP，以产生综合基因剂量效应（=个体SNP风险概况），这可能使基于药物遗传学的个体化治疗成为可能。
