Review paper 111 Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics John F. Deeken a , William D. Figg b , Susan E. Bates a and Alex Sparreboom b A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration–time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy. Anti-Cancer Drugs 18:111–126  c 2007 Lippincott Williams & Wilkins. Anti-Cancer Drugs 2007, 18:111–126 Keywords: anticancer drugs, pharmacogenetics, pharmacokinetics, toxicity a Medical Oncology Branch, Center for Cancer Research and b Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland, USA. Correspondence to A. Sparreboom, Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, DTRC, Mail Stop 314, Room D1034B, 332 North Lauderdale, Memphis, TN 38105, USA Tel: + 1 901 495 5346; fax: + 1 901 495 3125; e-mail: alex.sparreboom@stjude.org Sponsorship: This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland, USA. Disclaimer: The content of this paper does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Received 16 May 2006 Revised form accepted 6 September 2006 Introduction Individualizing therapy for patients being treated with pharmaceutical agents is an overarching goal of basic and clinical research in this first part of the 21st century. In no area of medicine is this goal more critical than in cancer chemotherapy. A better ability to predict which agents to use in individual patients and an improved means of dosing drugs are critical needs facing clinical researchers in oncology care. Many sources of interindividual variation exist in drug toxicity and efficacy, both pharmacokinetic and pharma- codynamic, as highlighted in Fig. 1. These include patients’ body size and composition, age, ethnicity, and sex, as well as physiologic aspects, especially disease state and organ function. Environmental factors include inter- actions with food, drinks, environmental toxins, other drugs (prescription, over-the-counter and herbal medica- tions), as well as interactions with drug formulation components. Finally, a patient’s genetic profile is a critical – but not the only – aspect to account for and explain inter patient variability in drug response. The pharmacogenetic differences between patients are also multifactorial, as shown in Fig. 2. One factor of growing importance as more targeted therapies are developed is polymorphisms in drug targets, including cell surface receptors and target proteins. Another is polymorphisms in hormonal-regulated enzymes. Finally, and the focus of this review, are polymorphisms in the genes involved in drug pharmacokinetics that impact drug absorption, distribution, metabolism and excretion. A growing body of research is highlighting the role that variations in the genes encoding drug-metabolizing enzymes and drug transporters play in explaining, at least in part, the substantial interindividual variability seen in the clinical profile of several important drugs. Severe toxicity might occur in the absence of normal metabolism of active compounds, whereas the therapeutic effect of a drug could be diminished in the absence of activation of a prodrug. Diminished efficacy could be due to the induction of metabolism enzymes or transporters, an induction that may be affected by genetic variation. The importance in detecting polymorphisms for a given 0959-4973  c 2007 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.