Part 3: Pharmacogenetic Variability in Phase II Anticancer Drug Metabolism

Learning Objectives After completing this course, the reader will be able to: Identify genetic variants of glutathione S‐transferase and uridine diphosphoglucuronosyl transferase that have been shown to affect clinical outcomes in patients with cancer and describe the general effects of these varian...

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Published in:The oncologist (Dayton, Ohio) Ohio), 2011-07, Vol.16 (7), p.992-1005
Main Authors: Deenen, Maarten J., Cats, Annemieke, Beijnen, Jos H., Schellens, Jan H.M.
Format: Article
Language:English
Subjects:
Age
Anticancer drugs
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antitumor agents
Clinical Pharmacology: Pharmacogenetics: Opportunities for Patient-Tailored Anticancer Therapy
Drug metabolism
Drugs
Enzymes
Gene polymorphism
Genetic Variation
Glutathione transferase
Humans
Liver
Methyltransferase
N-Acetyltransferase
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - metabolism
Oncology
Personalized medicine
Pharmacodynamics
Pharmacogenetics
Pharmacogenetics - methods
Phase II metabolism
Polymorphism, Genetic
Renal function
Sulfotransferase
Uridine
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Summary:Learning Objectives After completing this course, the reader will be able to: Identify genetic variants of glutathione S‐transferase and uridine diphosphoglucuronosyl transferase that have been shown to affect clinical outcomes in patients with cancer and describe the general effects of these variants with respect to standard treatment. Describe potential treatment considerations in patients with cancer who have genetic polymorphisms that affect Phase II metabolism of anticancer drugs. This article is available for continuing medical education credit at CME.TheOncologist.com Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug‐metabolizing enzymes (glutathione S‐transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N‐acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient‐tailored anticancer therapy are proposed. 摘要 等同的药物剂量可能会导致抗癌治疗反应在个体间存在很大的差异。已知可能影响某种药物的药理学反应的非遗传学因素包括年龄、性别、联合给药以及肝肾功能等。尽管如此，这些协变量并不能解释所有观察到的患者间的差异。患者中遗传素质的差异已被确定是药物反应差异的重要影响因素。由于遗传多态性可影响编码蛋白的表达与活性，它是造成药物代谢、药物转运以及药效学作用变异的一个关键协变量。 本系列关于遗传药理学变异的综述由四部分组成。第三部分重点介绍II相药物代谢酶（谷胱甘肽S‐转移酶、尿苷二磷酸葡萄糖醛酸转移酶、甲基转移酶、硫酸基转移酶以及N‐乙酰化转移酶）的遗传学变异，并讨论编码这些酶的基因遗传多态性对抗癌药物疗效的影响。基于文献综述，提出对患者进行个体化抗癌治疗的机会。 This third part of a four‐part series on pharmacogenetics focuses on genetic variability in phase II drug‐metabolizing enzymes (glutathione S‐transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N‐acetyltransferases) and discusses the effects of g
ISSN:1083-7159
1549-490X
DOI:10.1634/theoncologist.2010-0260