Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors

F Y Ahmed, S J Johnston, J Cassidy, T O'Kelly, N Binnie, G I Murray, A H van Gennip, N G G M Abeling, S Knight, H L McLeod

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Abstract

Purpose: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity.

Patients and Methods: patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m(2) twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients.

Results: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery, Plasma uracil changed from a median less than 0.2 mu mol/L before therapy ta 27.76 mu mol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples.

Conclusion: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme, The mechanism of inactivation is a, the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer. (C) 1999 by American Society of Clinical Oncology.

Original languageEnglish
Pages (from-to)2439-2445
Number of pages7
JournalJournal of Clinical Oncology
Volume17
Publication statusPublished - 1999

Keywords

  • 5-ETHYNYLURACIL 776C85
  • 5-FLUOROURACIL METABOLISM
  • FLUOROURACIL
  • CANCER
  • CHEMOTHERAPY
  • PHARMACOKINETICS
  • MODULATION
  • DEFICIENCY
  • CARCINOMA
  • MECHANISM

Cite this

Ahmed, F. Y., Johnston, S. J., Cassidy, J., O'Kelly, T., Binnie, N., Murray, G. I., ... McLeod, H. L. (1999). Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors. Journal of Clinical Oncology, 17, 2439-2445.

Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors. / Ahmed, F Y ; Johnston, S J ; Cassidy, J ; O'Kelly, T ; Binnie, N ; Murray, G I ; van Gennip, A H ; Abeling, N G G M ; Knight, S ; McLeod, H L .

In: Journal of Clinical Oncology, Vol. 17, 1999, p. 2439-2445.

Research output: Contribution to journalArticle

Ahmed, FY, Johnston, SJ, Cassidy, J, O'Kelly, T, Binnie, N, Murray, GI, van Gennip, AH, Abeling, NGGM, Knight, S & McLeod, HL 1999, 'Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors', Journal of Clinical Oncology, vol. 17, pp. 2439-2445.
Ahmed, F Y ; Johnston, S J ; Cassidy, J ; O'Kelly, T ; Binnie, N ; Murray, G I ; van Gennip, A H ; Abeling, N G G M ; Knight, S ; McLeod, H L . / Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors. In: Journal of Clinical Oncology. 1999 ; Vol. 17. pp. 2439-2445.
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abstract = "Purpose: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity.Patients and Methods: patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m(2) twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients.Results: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery, Plasma uracil changed from a median less than 0.2 mu mol/L before therapy ta 27.76 mu mol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples.Conclusion: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme, The mechanism of inactivation is a, the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer. (C) 1999 by American Society of Clinical Oncology.",
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T1 - Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors

AU - Ahmed, F Y

AU - Johnston, S J

AU - Cassidy, J

AU - O'Kelly, T

AU - Binnie, N

AU - Murray, G I

AU - van Gennip, A H

AU - Abeling, N G G M

AU - Knight, S

AU - McLeod, H L

PY - 1999

Y1 - 1999

N2 - Purpose: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity.Patients and Methods: patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m(2) twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients.Results: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery, Plasma uracil changed from a median less than 0.2 mu mol/L before therapy ta 27.76 mu mol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples.Conclusion: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme, The mechanism of inactivation is a, the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer. (C) 1999 by American Society of Clinical Oncology.

AB - Purpose: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity.Patients and Methods: patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m(2) twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients.Results: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery, Plasma uracil changed from a median less than 0.2 mu mol/L before therapy ta 27.76 mu mol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples.Conclusion: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme, The mechanism of inactivation is a, the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer. (C) 1999 by American Society of Clinical Oncology.

KW - 5-ETHYNYLURACIL 776C85

KW - 5-FLUOROURACIL METABOLISM

KW - FLUOROURACIL

KW - CANCER

KW - CHEMOTHERAPY

KW - PHARMACOKINETICS

KW - MODULATION

KW - DEFICIENCY

KW - CARCINOMA

KW - MECHANISM

M3 - Article

VL - 17

SP - 2439

EP - 2445

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

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