Introduction

The therapeutic index of most cytotoxic agents is still a matter of concern because drug activity against malignant cells is associated with toxicity to normal tissues. In addition to this, new drugs designed to inhibit specific molecular pathways critical to tumor cell survival, such as imatinib and gefitinib (1), are susceptible to therapeutic failure due to target mutation or downregulation with activation of alternative signal transduction pathways. Recent progress in analytical techniques and the sequencing of the human genome has allowed the discovery of gene variants involved in pharmacokinetic and pharmacodynamic pathways (Fig. 1), which define cancer chemosensitivity and/or drug tolerability (2).

Two branches of pharmacology have benefited from the completion of the human genome project: pharmacogenetics, the study of the genetic basis of drug response, and pharmacogenomics, the genome-wide analysis of cell and tissues to identify complex genetic alterations underlying drug responses not explained by the classical pharmaco-genetic approach or to discover novel targets for drug development. A simple classification of genetic variability includes:

1. Genetic alterations occurring at low frequency, whose effects suddenly arise and negatively affect cell function (i.e., inactivating mutations affecting genes, which encode for drug-metabolizing enzymes).

2. Sequence variants situated at well-defined positions along the gene (i.e., single-nucleotide polymorphisms, SNPs), appearing at higher frequency in the case population than that of casually occurring mutations. SNPs may affect exons (i.e., the effect may be the change in the amino acid sequence), introns (likely causing the insertion of alternative splicing sites), or the regulatory region of the gene (with alteration of gene expression) (Fig. 2).

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