Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy.
Oxaliplatin is a relatively new platinum analogue that is currently used in pharmacotherapy of metastatic colorectal cancer. Its dose-limiting toxicity is sensory neuropathy, which can be modulated by infusion of calcium and magnesium. Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well. If they are not removed from DNA, oxaliplatin adducts are lethal. Cellular defense mechanisms prevent adduct formation (e.g., glutathione-S-transferase) or remove DNA adducts (e.g., nucleotide excision repair). Depending on the activity of necessary enzymes in these cellular defense pathways, oxaliplatin induced damage varies from one individual to another. There is growing evidence that polymorphisms in genes coding for DNA repair enzymes and metabolic inactivation routes contribute to the interindividual differences in anti-tumour efficacy and toxicity of oxaliplatin. Single nucleotide polymorphisms (SNPs) may yield inactive enzymes, or increased gene transcription and hence increased enzyme production. This review covers findings of recent investigations on the associations of SNPs and clinical outcome after oxaliplatin chemotherapy in metastatic colorectal cancer.
Kweekel
D M
DM
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. D.M.Kweekel@lumc.nl
Gelderblom
H
H
Guchelaar
H-J
HJ
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D018773:Genes, erbB-1; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005982:Glutathione Transferase