Dihydropyrimidine dehydrogenase activity in cancer patients

Milano, Gérard; Gaspard, M; Thyss, A.; Renée, Nicole; Schneider, M.; Démard, F; Fleming, Ronald A.; Bargnoux, P.-J.; Plagne, R

doi:10.1016/s0959-8049(05)80358-2

Cited by 47 publications

(41 citation statements)

References 16 publications

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“…In 2002, the estimated cost incurred for the care of cancer patient with 5-FU toxicity, in the United States, ranged from $30 000 to $100 000 per patient, resulting in an annual treatment cost of $36-145 million. 13 C]-uracil catabolic pathway (adapted from [24]).…”

Section: Introductionmentioning

confidence: 99%

“…. 13 CO 2 breath patterns from two healthy volunteers after administration of a fixed 300 mg dose (A) and a weight-adjusted (6 mg kg −1 ) dose (B) of 2-13 C-uracil. Less variability was observed in breath patterns when the dose of 2-13 C-uracil was standardized to weight (6 mg kg −1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Approximately 85% of the administered 5-FU dose is inactivated in the liver through the enzymes of the uracil catabolic pathway, DPD, dihydropyrimidinase (DHP) and β-ureidopropionase (BUP-1) [8][9][10][11]. Deficient uracil catabolism has been associated with 5-FU dose-related toxicity, including severe gastrointestinal, hematological and neurological toxicity which at times includes cerebellar ataxia and coma [9,[12][13][14][15][16][17][18][19][20][21][22]. Currently, no rapid or reliable non-invasive diagnostic breath tests are available for the detection of deficient uracil/fluorouracil catabolism or the risk of developing severe 5-FU-related toxicities.…”

Section: Introductionmentioning

confidence: 99%

“…During the last several years our research has focused on developing an oral-uracil breath test (UraBT) to predict 5-FU toxicity resulting from deficient uracil catabolism. This BT utilized an orally administered pyrimidine ([2-13 C]-uracil) that is metabolized via the same catabolic pathway as 5-FU, to release 13 CO 2 metabolite which can be quantified via infrared spectrometry in the breath (figure 1). Individuals with deficient uracil catabolism are identified by reduced breath 13 CO 2 concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…Below is a review of several studies that describe the development, validation and application of the UraBT in healthy volunteers and cancer patients. These studies investigate the association between uracil catabolic activity, breath 13 CO 2 concentrations and plasma 13 C-uracil pharmacokinetics [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

¹³ C-5-FU breath test current status and future directions: a comprehensive review

Ezzeldin¹,

Acosta²,

Mattison³

et al. 2009

J. Breath Res.

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Breath tests (BTs) represent a safe non-invasive alternative strategy that could provide valuable diagnostic information in conditions like fat malabsorption, carbohydrate (lactose and fructose) malabsorption, liver dysfunction, impaired gastric emptying, abnormal small bowel transit time, small intestinal bacterial overgrowth and Helicobacter pylori infection. To date, despite the availability of a number of breath tests, only three have gained approval by the FDA for application in a clinical setting ((13)C-urea breath test for the detection of H. pylori; NO breath test for monitoring asthma and alkane breath test for heart transplant rejection). Unfortunately, none of these tests investigate cancer patients or response to cancer chemotherapy. Several years ago it was realized that the presence of a reliable non-invasive approach could assist in the detection of patients at risk of developing severe life-threatening toxicities prior to the administration of fluoropyrimidines (e.g. 5-FU) or related cancer chemotherapy. 5-FU toxicity results mainly from deficient uracil catabolism. This review discusses the development of a BT that utilizes an orally administered pyrimidine ([2-(13)C]-uracil) which is metabolized via the same catabolic pathway as 5-FU. This ([2-(13)C]-uracil) breath test could provide a valuable addition to the patients' standard of care.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

¹³ C-5-FU breath test current status and future directions: a comprehensive review

Ezzeldin¹,

Acosta²,

Mattison³

et al. 2009

J. Breath Res.

View full text Add to dashboard Cite

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A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

Vainchtein

Rosing

Schellens

et al. 2009

Biomedical Chromatography

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A rapid and selective liquid chromatography/tandem mass spectrometric method was developed for the simultaneous determination of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouracil (5'-DFUR), 5-fluorouracil (5-FU) and dihydro-5-fluorouracil (FUH(2)) in human plasma. A 200 microL human plasma aliquot was spiked with a mixture of internal standards fludarabine and 5-chlorouracil. A single-step protein precipitation method was employed using 10% (v/v) trichloroacetic acid in water to separate analytes from bio-matrices. Volumes of 20 microL of the supernatant were directly injected onto the HPLC system. Separation was achieved on a 30 x 2.1 mm Hypercarb (porous graphitic carbon) column using a gradient by mixing 10 mm ammonium acetate and acetonitrile-2-propanol-tetrahydrofuran (1 : 3 : 2.25, v/v/v). The detection was performed using a Finnigan TSQ Quantum Ultra equipped with the electrospray ion source operated in positive and negative mode. The assay quantifies a range from 10 to 1000 ng/mL for capecitabine, from 10 to 5000 ng/mL for 5'-DFCR and 5'-DFUR, and from 50 to 5000 ng/mL for 5-FU and FUH(2) using a plasma sample of 200 microL. Correlation coefficients (r(2)) of the calibration curves in human plasma were better than 0.99 for all compounds. At all concentration levels, deviations of measured concentrations from nominal concentration were between -4.41 and 3.65% with CV values less than 12.0% for capecitabine, between -7.00 and 6.59% with CV values less than 13.0 for 5'-DFUR, between -3.25 and 4.11% with CV values less than 9.34% for 5'-DFCR, between -5.54 and 5.91% with CV values less than 9.69% for 5-FU and between -4.26 and 6.86% with CV values less than 14.9% for FUH(2). The described method was successfully applied for the evaluation of the pharmacokinetic profile of capecitabine and its metabolites in plasma of treated cancer patients.

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Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

Barberi‐Heyob

Weber

Merlin

et al. 1995

Cancer Chemother. Pharmacol.

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This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m2 per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m2). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by high-performance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUCFUrd) and for FdUrd (AUCFdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUCFUrd values (mean +/- SEM, 2.9 +/- 0.7 micrograms ml-1 h) and high AUCFdUrd values (14.1 +/- 2.7 micrograms ml-1 h), respectively, whereas courses with myelosuppression (WHO grades 2-4) showed inverse profiles with high AUCFUrd values (16.3 +/- 2.3 micrograms ml-1 h) and low AUCFdUrd values (3.1 +/- 1.0 micrograms ml-1 h), respectively. A statistically significant difference in AUCFdUrd values was also observed between cycles with and those without mucositis (P = 0.0027), with AUCFdUrd values being 22.6 +/- 5.6 and 7.8 +/- 1.9 micrograms ml-1 h, respectively. Whereas hematotoxicity could be correlated with both AUCFUrd and AUCFdUrd values, mucositis was associated with high AUCFdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P = 0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.

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Dihydropyrimidine dehydrogenase activity in cancer patients

Cited by 47 publications

References 16 publications

¹³ C-5-FU breath test current status and future directions: a comprehensive review

¹³ C-5-FU breath test current status and future directions: a comprehensive review

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

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Dihydropyrimidine dehydrogenase activity in cancer patients

Cited by 47 publications

References 16 publications

13 C-5-FU breath test current status and future directions: a comprehensive review

13 C-5-FU breath test current status and future directions: a comprehensive review

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

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¹³ C-5-FU breath test current status and future directions: a comprehensive review

¹³ C-5-FU breath test current status and future directions: a comprehensive review