A novel mutant allele of the CYP2A6 gene (CYP2A6*11) found in a cancer patient who showed poor metabolic phenotype towards tegafur

Daigo, Satoshi; Takahashi, Yoshiki; Fujieda, Masaki; Ariyoshi, Noritaka; Yamazaki, Hiroshi; Koizumi, Wasaburo; Tanabe, Satoshi; Saigenji, Katsunori; Nagayama, Shigeya; Ikeda, Kazumasa; Nishioka, Yasuhiko; Kamataki, Tetsuya

doi:10.1097/00008571-200206000-00005

Cited by 109 publications

(74 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, mutations in CYP2A6 have recently been identified to affect tegafur metabolism. 59 Two mutant alleles, CYP2A6*4C and CYP2A6*11, were detected in a patient with largely reduced tegafur clearance. The prevalence of these mutations and its impact on clinical outcome are not yet clear.…”

Section: Capecitabine and Tegafurmentioning

confidence: 95%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Section: Capecitabine and Tegafurmentioning

confidence: 95%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Concerning anticancer drugs, CYP2A6 catalyses the activation of tegafur to 5-fluorouracil, a drug commonly used for colorectal cancer. In one study, a patient having a poor tegafurmetabolizing phenotype was found to be heterozygous for CYP2A6*4 and CYP2A6*11 (Daigo et al, 2002). However, CYP2C8 and CYP1A2 also catalyse the activation of tegafur (Komatsu et al, 2000) and further investigations are needed to clarify the impact of CYP2A6 polymorphisms on anticancer drug metabolism.…”

Section: Cyp2a6mentioning

confidence: 99%

Cytochrome P450 pharmacogenetics and cancer

2006

View full text Add to dashboard Cite

The cytochromes P450 (CYPs) are key enzymes in cancer formation and cancer treatment. They mediate the metabolic activation of numerous precarcinogens and participate in the inactivation and activation of anticancer drugs. Since all CYPs that metabolize xenobiotics are polymorphic, much emphasis has been put on the investigation of a relationship between the distribution of specific variant CYP alleles and risk for different types of cancer, but a consistent view does not yet exist. This is to a great extent explained by the fact that the CYPs involved in activation of precarcinogens are in general not functionally polymorphic. This is in contrast to CYPs that are active in drug biotransformation where large interindividual differences in the capacity to metabolize therapeutic drugs are seen as a consequence of polymorphic alleles with altered function. This includes also some anticancer drugs like tamoxifen and cyclophosphamide metabolized by CYP2D6, CYP2C19 and CYP2B6. Some P450 forms are also selectively expressed in tumours, and this could provide a mechanism for drug resistance, but also future therapies using these enzymes as drug targets can be envisioned. This review gives an upto-date description of our current knowledge in these areas.

show abstract

“…Tegafur, a cytotoxic component of S-1, is converted to 5FU by cytochrome P450 2A6 (CYP2A6). Racial differences for gene polymorphism of CYP2A6 have been identified (Daigo et al, 2002;M. Nakajima et al, 2006), and the variants are more frequent in Asians than in Caucasians (M. Nakajima et al, 2006).…”

Section: Advanced Settingmentioning

confidence: 99%

Multimodal Therapies for Upper Gastrointestinal Cancers – Past, Now, and Future

Shimoyama¹

2011

Current Cancer Treatment - Novel Beyond Conventional Approaches

View full text Add to dashboard Cite

A novel mutant allele of the CYP2A6 gene (CYP2A6*11) found in a cancer patient who showed poor metabolic phenotype towards tegafur

Cited by 109 publications

References 31 publications

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Cytochrome P450 pharmacogenetics and cancer

Multimodal Therapies for Upper Gastrointestinal Cancers – Past, Now, and Future

Contact Info

Product

Resources

About