title: Part 4: pharmacogenetic variability in anticancer pharmacodynamic drug effects.
abstract: Response to treatment with anticancer drugs is subject to wide interindividual variability. This variability is expressed not only as differences in severity and type of toxicity, but also as differences in effectiveness. Variability in the constitution of genes involved in the pharmacokinetic and pharmacodynamic pathways of anticancer drugs has been shown to possibly translate into differences in treatment outcome. The overall knowledge in the field of pharmacogenetics has tremendously increased over the last couple of years, and has thereby provided opportunities for patient-tailored anticancer therapy. In previous parts of this series, we described pharmacogenetic variability in anticancer phase I and phase II drug metabolism and drug transport. This fourth part of a four-part series of reviews is focused on pharmacodynamic variability and encompasses genetic variation in drug target genes such as those encoding thymidylate synthase, methylene tetrahydrofolate reductase, and ribonucleotide reductase. Furthermore, genetic variability in other pharmacodynamic candidate genes involved in response to anticancer drugs is discussed, including genes involved in DNA repair such as those encoding excision repair crosscomplementing group 1 and group 2, x-ray crosscomplementing group 1 and group 3, and breast cancer genes 1 and 2. Finally, somatic mutations in KRAS and the gene encoding epidermal growth factor receptor (EGFR) and implications for EGFR-targeted drugs are discussed. Potential implications and opportunities for patient and drug selection for genotype-driven anticancer therapy are outlined.
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014644:Genetic Variation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic
chemical_list: D000970:Antineoplastic Agents