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Cancer Pharmacogenetics: Polymorphisms, Pathways and Beyond

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Cancer Pharmacogenetics: Polymorphisms, Pathways and Beyond REVIEWS CANCER PHARMACOGENETICS: POLYMORPHISMS, PATHWAYS AND BEYOND Cornelia M. Ulrich*, Kim Robien* and Howard L. McLeod‡ Inherited genetic variations can affect a patient’s response to chemotherapeutic agents given for cancer. Pharmacogenetics aims to use knowledge of these variations to ‘tailor’ therapy for improved response and reduced toxicity. Most research so far has focused on single polymorphisms. A more comprehensive approach to predict treatment response will be to consider genetic variation in entire biological and pharmacological pathways. Of particular relevance to cancer chemotherapy is folate metabolism, which is the target of methotrexate and 5-fluorouracil. Furthermore, efforts have begun to construct pathways of genes that have pharmacological relevance for individual chemotherapeutic agents. Together, these pathway strategies offer a higher likelihood of achieving the promise of genetically guided cancer therapy. THERAPEUTIC INDEX With increasingly comprehensive information available polymorphism results in significant changes in the abil- The ratio of the median lethal dose from the Human Genome Project, pharmacogenetics ity to metabolize drugs. However, it is possible that the to the median effective dose for a — the science of incorporating information on inherited combination of several polymorphisms in components given medication. Used to describe genetic variability into predicting treatment response — of a ‘biological’ pathway or ‘pharmacological’ pathway the dose range over which a drug has a therapeutic effect without is flourishing. A better understanding of pharmacoge- might significantly influence therapeutic response. FOLATE unacceptable toxicity. netic associations is especially important in cancer metabolism has been the target for several key chemo- chemotherapy, as many chemotherapeutic agents given therapeutic agents, and is an example of a biological POLYMORPHISM for cancer are characterized by a narrow THERAPEUTIC pathway with pharmacogenetic relevance2. Variation within a gene (often at INDEX1. POLYMORPHISMS in both the individual’s genome, as This review will illustrate the relative contribution of a single nucleotide) where two 1 or more alleles exist at a well as the tumour genome, will affect drug response — genetic variation in individual candidate genes within a frequency of at least 1% in the tumours are expected to be of the same genetic makeup biological pathway to patient toxicity and therapeutic general population. with respect to specific polymorphic sites as somatic outcome, and show how genetic variability in both tissue, unless new mutations have occurred or the site is biological and pharmacological pathways can affect treat- subject to chromosomal loss.Yet, drug-related toxicity ment response. In addition, novel strategies for pharma- almost exclusively depends on the genotype of non- cogenetic discovery will be described as we try to move *Fred Hutchinson Cancer tumour tissue1. So, inherited polymorphisms will have a beyond the limitations of our current understanding of Research Center, Cancer key role with respect to toxicity, a crucial dose-limiting the genetic mechanisms that regulate drug activity. Prevention Research factor in most cancer chemotherapy regimens. Program, Seattle, Washington 98109,USA. Research that has used single polymorphisms as Single-gene/single-variant pharmacogenetics ‡Washington University, markers of variation in treatment response has been The classical approach to identifying a genetic basis for Department of Medicine, promising, but has lead to some conflicting results. extreme drug toxicity or aberrant drug effect has served St Louis, Missouri Many of the variant forms of drug-metabolizing us well during the initial phase of pharmacogenetic 63130, USA. Correspondence to C.M.U. enzymes show only a small deviation from wild-type research; a clinical phenotype — such as altered phar- e-mail: [email protected] enzyme activity, and are part of polygenic metabolic or macokinetics or extreme toxicity — has been used to doi:10.1038/nrc1233 pharmacological pathways. It is quite rare that a single identify PROBANDS, followed by evaluation of genetic 912 | DECEMBER 2003 | VOLUME 3 www.nature.com/reviews/cancer REVIEWS Summary However, many of the genetic variants that are associated with extreme drug toxicity are uncom- • The field of pharmacogenetics attempts to use genetic information to predict an mon, and therefore explain only a small proportion individual’s drug response. It is especially important in cancer chemotherapy given the of the population variance that is seen in drug narrow therapeutic index of these drugs. response. In addition, it is recognized that most drug • So far, pharmacogenetic research has largely focused on the effect of single candidate effects are polygenic in nature. Genetic polymor- polymorphisms. However, many of the genetic variants that are associated with phisms have been identified in 93% of all known extreme drug toxicity are rare and explain only a small portion of the variation seen in genes, with two coding-region single-nucleotide drug response. polymorphisms (SNPs) observed in most genes that • Understanding the interactions of genetic variants within a biological or have been evaluated so far17,18. The initial SNP map pharmacological pathway will allow for an improved ability to predict drug response. from the Human Genome Project discovered 1.42 • Folate metabolism — a target of antifolate chemotherapeutic agents and million variants, with the public databases, which are thymidylate-synthase inhibitors — is a biological pathway of substantial interest to growing rapidly, now containing over 5 million pharmacogenetic researchers. human SNPs. Research on the impact of common • Pharmacological pathways are being constructed for the systematic evaluation of the genetic variants on drug response is just beginning, genes that regulate variation in the toxicity and efficacy of anticancer agents. and will constitute a considerable research effort over • Mouse models show promise in identifying key enzymes in pharmacogenetic pathways the next years. and will allow study of genetic variation in these pathways. The biological-pathway approach Most enzymes function in complex networks with sev- eral regulatory mechanisms. So, it is unlikely that any polymorphisms, for example in the drug-metabolizing one variant with modest effects on enzyme function will enzyme that is responsible for the degradation of the affect disease or treatment outcomes, whereas the com- drug. These genetic polymorphisms include nucleotide bination of several variants within the same pathway repeats, deletions, insertions and mutations that influence might result in significant disturbances. Alternatively, gene expression and/or function3. several genetic variants might cancel each other out and Genetic variants within a specific candidate gene diminish differences in the response that is associated provide the mechanistic basis for many of the early with a single polymorphic allele. An example of a bio- examples in pharmacogenetics. For instance, muta- logical pathway with relevance to cancer chemotherapy tions or deletions in the CYTOCHROME P450 enzyme is folate metabolism. CYP2D6 occur in the general population and about 10% have been associated with a poor-metabolizer Folate metabolism and antifolates. Folate acts as a phenotype4. This is important for codeine and related donor for methyl groups, such as in the conversion of pain medications, as the activation of codeine to homocysteine to methionine — a precursor for the morphine is dependent on the catalytic function of universal methyl donor S-adenosyl-methionine — CYP2D6 (REF. 5). Patients with low CYP2D6 activity and in the synthesis of purines and pyrimidines19 FOLATE do not receive pain relief from codeine or other ana- (FIG. 1). Therefore, folate has a key role in normal cell 5 One of the B vitamins. The logues, because they are not able to form morphine . growth and replication and has been an attractive primary role of this B vitamin is As another example, polymorphisms in thiopurine target for chemotherapeutic agents. Antifolate agents as a carrier of methyl groups, methyltransferase and dihydropyrimidine dehydro- are drugs that target specific enzymes in folate especially for purine, pyrimidine genase have been associated with altered drug metabolism (for example, dihydrofolate reductase) and methionine synthesis. metabolism and increased risk of severe toxicity and are used for the treatment of various cancers, PROBAND from the anticancer agents 6-mercaptopurine and including haematological, colorectal, breast and An individual with the condition 5-fluorouracil, respectively 6–10. In addition, a variant pancreatic malignancies. of interest, who serves as the number of dinucleotide-repeat sequences (5–8 Methotrexate and 5-fluorouracil are folate-pathway starting point for exploration of ′ a family pedigree for the genes repeats) in the promoter for uridine 5 -diphosphate- inhibitors that have been available for 50 years and con- that are responsible for the glucuronosyltransferase 1A1 (UGT1A1) has an influ- tinue to be used in various treatment regimens for cancer condition. ence on in vitro and in vivo glucuronidation of and autoimmune diseases. Their specific mechanisms of SN-38, the active metabolite of irinotecan11. Patients action have been reviewed previously20,21. Folate ana- CYTOCHROME-P450 ENZYMES with seven repeat sequences have a fourfold relative logues
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