1. ¹Department of Pharmacy, Diaconessen Hospital Meppel & Bethesda Hospital Hoogeveen, Meppel, The Netherlands
2. ²Department of Pulmonary Diseases, University of Groningen & University Medical Center Groningen, Groningen, The Netherlands
3. ³Department of Pharmacy, University of Groningen & University Medical Center Groningen, Groningen, The Netherlands
4. ⁴Department of Medical Oncology, University of Groningen & University Medical Center Groningen, Groningen, The Netherlands

Correspondence: Dr JG Maring, Department of Pharmacy, Diaconessen Hospital Meppel & Bethesda Hospital Hoogeveen, Hoogeveenseweg 38, 7943KA Meppel, The Netherlands. Tel: +31 522 234900; Fax: +31 522 243900; E-mail: maring@diacmeppel.nl

Received 17 December 2004; Revised 3 May 2005; Accepted 5 May 2005.

Abstract

Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumour-specific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5'-nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.