Genetic factors influencing Pyrimidine-antagonist chemotherapy

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, tumourspecific 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 0 -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.

Identification of a novel single nucleotide polymorphism in the first tandem repeat sequence of the thymidylate synthase 2R allele

“…Many fluoropyrimidine prodrugs, such as 5-fluorouracil (5-FU) and capecitabine exert their antitumor effects by inhibiting TS, and are commonly used in the treatment of colon, breast, head and neck cancers. 1 Individual response and associated side effects to these drugs are often variable and have been shown to depend at least in part on the expression level of TS in both malignant and normal tissues. Low TS expression has consistently been shown to predict for better efficacy of 5-FU treatment in colorectal cancer, but has also been associated with increased toxicity because of cytotoxic damage to normal tissues.…”

Prediction of clinical outcome of S-1-based chemotherapy for gastric cancer patients

“…1). CYP2A6 is the main CYP450 enzyme involved in tegafur activation, but CYP1A2 and CYP2C8 also play a signifi cant role [6].…”

“…1). CYP2A6 is the main CYP450 enzyme involved in tegafur activation, but CYP1A2 and CYP2C8 also play a signifi cant role [6].In humans, 80%-90% of the administered 5-FU is catabolized rapidly to the inactive metabolite α-fl uoroAbstract S-1, an oral fl uoropyrimidine has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard chemotherapy option. Individual variations in the enzyme activity of the 5-FU metabolic pathway can affect the extent of 5-FU metabolism and affect the effi cacy of S-1 based chemotherapy.…”

Genetic Bases for Predisposition to Common Multifactorial Disease in Man. Part II

“…To date, at least 34 DPD variants have been reported. To prevent toxicity and increase effi cacy of therapy with 5-FU, it is considered that an analysis of DNA polymorphisms complemented with analysis of the plasma concentrations of DPD is indicated (19,41,53).…”