Population study of dihydropyrimidine dehydrogenase in cancer patients.

Etienne, Marie‐Christine; Lagrange, Jean‐Léon; Dassonville, O.; Fleming, Ronald A.; Thyss, A.; Renée, Nicole; Schneider, M; Démard, F; Milano, Gérard

doi:10.1200/jco.1994.12.11.2248

Cited by 388 publications

(252 citation statements)

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“…This offers useful themes for undertaking larger prospective pharmacogenetic studies in the future. Regarding DPD deficiency, it is increasingly being recognized as an important pharmacogenetic factor in the aetiology of severe 5-FU associated toxicity (6,18,19). Only one heterozygous subject for this mutation was detected, indicating a low prevalence of the mutation (1.7%) in concordance with previous studies (6).…”

Section: Discussionsupporting

confidence: 86%

Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer

Salgado¹,

Zabalegui²,

Gil³

et al. 2007

Oncol Rep

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Abstract.Pharmacogenetics is an increasingly useful field where the genetic studies are becoming an important tool for predicting drug toxicity and/or efficacy. Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene polymorphisms could be highly informative tools in the clinical handling of colorectal cancer patients, who are following fluoropyrimidine based chemotherapy. Fifty-eight patients, with non-resectable metastatic colorectal cancer, were treated with capecitabine and raltitrexed, every three weeks. Patients were divided in a good-response group (complete and partial response) and a poor-response group (stable and progression). A genotype panel TS-DPD was evaluated. Results show that TS genotype analysis clearly differentiates patients with a worst response to a 5-fluorouracil based chemotherapy. DPD genotype was shown to be highly informative for prediction of toxicity of the treatment. These polymorphisms could represent an accurate, rapid and effective determination panel, indicative of resistance and toxicity for patients undergoing fluoropyrimidine based treatment.

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Section: Discussionsupporting

confidence: 86%

Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer

Salgado¹,

Zabalegui²,

Gil³

et al. 2007

Oncol Rep

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“…In addition, it was also noted that stomatitis occurred more commonly (P < 0.003) in women. Previously, it has been reported that DPD activity is 15% lower in women (Etienne et al, 1994) and this might lead to a gender difference in plasma 5FU concentrations, as described by Vokes et al (1996). Also, in the Vokes study, higher 5FU concentrations were associated with an increase in mucositis.…”

Section: Relationships Of 5fu Concentration Patient Characteristics mentioning

confidence: 80%

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

et al. 2001

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Summary PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425-432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47-53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter-and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m −2 day −1 ) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to 'exposure-guided' 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand-foot syndrome was the most common dose limiting toxicity. Variability in 5FU 300 Css was considerably less than previously reported; 94 ± 25 ng ml −1 (CV = 27%). No relationships were demonstrated between subject mean 5FU 300 Css and PD end-points such as response, mucositis, diarrhoea and hand-foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer.

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“…[48][49][50] In patients who are deficient for DPD, 5-FU clearance is dramatically reduced and standard doses of 5-FU cause excessive toxicity in these patients. 48,51,52 The frequency of DPD deficiency has been estimated to be as high as 2-3% in Caucasians based on measurements of DPD activity in peripheral mononuclear cells in patients and healthy volunteers 53,54 This percentage is probably high enough to justify screening on DPD deficiency prior to 5-FU-based chemotherapy. Instead of screening for specific mutations in the DPYD gene, Mattison et al 55 developed a simple uracil breath test for DPD phenotyping, based on the release of 13 CO 2 from 2-13 C uracil in the presence of intact DPD.…”

Section: -Fluorouracilmentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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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.

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Population study of dihydropyrimidine dehydrogenase in cancer patients.

Cited by 388 publications

References 0 publications

Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer

Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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