Pharmacogenetics for individualized cancer chemotherapy
Section snippets
Pharmacogenetics and the human genome
It is a well-known clinical observation that the same doses of medication cause considerable heterogeneity in efficacy and toxicity across human populations (Evans & Relling, 1999, Fagerlund & Braaten, 2001). This heterogeneity can lead to unpredictable life-threatening or even lethal adverse effects in small groups of patients (Rothenberg et al., 2001, Sargent et al., 2001). The interindividual variability in drug response cannot satisfactorily be explained by factors such as renal and liver
Types of genetic alterations
Polymorphisms represent common variations in a DNA sequence that may lead to reduced activity of the encoded gene, but in some cases, also to increased activities (Evans & Relling, 1999). Unlike somatic mutations, they are stable and heritable. Polymorphisms include single nucleotide polymorphisms (SNPs), micro- and minisatellites. An SNP represents a single base exchange that may or may not cause an amino acid exchange in the encoded protein. The frequency of SNPs is greater than 1% in a
Multiplicity of mechanisms
As described previously, drug resistance to cytostatic drugs is determined by multiple factors (Efferth et al., 1992, Efferth & Volm, 1993, Volm et al., 1993, Volm et al., 2002a, Volm et al., 2002b, Volm et al., 2004, Verrills & Kavallaris, 2003). Despite the fact that anticancer drugs are extremely divergent in their chemical and physical structures and biological actions, a synopsis of the relevant mechanisms, which influence drug effects, allows to categorize them as to whether they act
Drug pathway profiling
The current candidate gene-based approaches require the a priori knowledge and selection of a small number of candidate genes for hypothesis testing. Complex human disorders such as cancer are caused by multiple genetic factors rather than by single causes. This hampers the reliable prediction of tumor drug response and normal tissue toxicity because the understanding of the precise role of all participating factors is still limited. Genome-wide linkage analyses may be a more systematic
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