Pharmacokinetics Pharmacodynamics

Figure 1 Influence of genetic factors on the pharmacokinetics and pharmacodynamics of anticancer agents. Abbreviations: SNPs, single-nucleotide polymorphisms; Emax, maximum effect (sigmoid effect model); ANC, absolute neutrophil count.

Genetic analysis is based on a wide variety of techniques suitable to decipher the alterations of genetic material (SNP, deletion or duplication of a few genes up to chromosomal rearrangements); and the recent development of DNA microarray technology will enable genome-wide screening for diagnostic purposes (3,4).

The identification of candidate genes for pharmacogenetic analysis is a complex process because the activity of anticancer drugs is influenced by (1) metabolic activation and inactivation (i.e., CYP450 and UGT), (2) expression of drug targets [i.e., thymidylate synthase and epidermal growth factor receptor (EGFR)], (3) integrity of pathways that recognize the cellular damage and promote or inhibit apoptosis (i.e., p53 and Bcl-2), (4) DNA repair systems (i.e., ERCC1, XPD), and (5) active drug transport outside the cell (i.e., ABC transporters) (5,6).

Codons Codons

Nucleotide(s) deletion: -ATA-cGg-ATT-CGG- -ATA-GGA-TTC-GG...

Nucleotide(s) insertion: -ATA-'CGG-ATt*-CGG- -ATA-CCg-GAT-TCG-G...

Microsatellites (SLP): -CTG-TAT-ATA-TAT-ATA-GGT-

-CTG-TAT-ATA-TAT-ATA-TAT-ATA-GGT--CTG-TAT-ATA-TAT-ATA-TAT-ATA-TAT-ATA-GGT-

Figure 2 Major causes of genetic variability; nucleotide deletions or insertions are responsible for frame shifts, whereas microsatellites, affecting the regulatory regions of the gene, are associated with variability in translation efficiency. SNP may be silent or associated with amino acid change in the encoded protein. Abbreviations: SNP, single-nucleotide polymorphism; SLP, sequence length polymorphism.

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