23 Pharmacogenetics of Cancer and DNA Repair Enzymes

Pharmacogenetics is focused on finding associations between drug response and the genetic background of a patient.38 Resequencing of the human genome revealed that nucleotide variation between individuals exists in 0.1% of the genome, which corresponds to 3 million differences. These variations occur in more than 1% of a population and are designated as single nucleotide polymorphisms (SNP), normally not causing any disease. Functional variants caused by SNPs in drug related genes (such as metabolism enzymes, transporters and receptors) have become of interest more and more in recent years.21,22,40,73 Variations that occur less frequent than 1% are designated as mutations and could be disease causing. Pharmacogenetic research has been expanded dramatically, with 1334 publications in the past century starting from 1961, while 7654 papers have been published since the year 2000 (pubmed accession date: November 18, 2010). The ultimate goal of pharmacogenetic research is the establishment of personalized medicine, aiming in prescribing the best choice of drug with the optimal concentration.67 Even the route of administration could be considered. At present, pharmacogenetics is not applied widely in clinical practice as a diagnostic tool, but is mainly restricted to research, which is, finding associations between drug response and genetic background within a group of patients. Much research is being performed in order to achieve a more beneficial cancer therapy, although pharmacogenetic research is also active in other fields like rheumatoid arthritis,7,42,52 transplantation50,84 and diabetes.19,51 The application of whole genome techniques for predicting patients’ sensitivity or resistance to a drug is the definition of pharmacogenomics.27,68 At present, most pharmacogenetic research is focused on enzymes that control the metabolism and uptake of many clinically used drugs. Most of these drugs are metabolized by Cytochrome P450 of which variant alleles are common that affects drug effectiveness.15,24,33 Roche diagnostics has developed an array to screen for the most important SNPs in Cytochrome P450 isoenzyme 2D6.72 This array is the first one that is approved by FDA for diagnostic testing. Other interesting genes with relatively high frequency of variant alleles are transporters such as MDR1.5,41,70 Affymetrix had developed an array (DMET) to screen for 1936 SNPs in genes that are involved in drug metabolism, uptake and detoxification.16