Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by eniluracil (GW776C85) in primary and metastatic colorectal cancer

Martin J. Heslin, Jieming Yan, Heidi Weiss, Lingning Shao, Jill Owens, V. Sol Lucas, Robert B. Diasio

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Purpose: Catabolism of 5-fluorouracil (5-FU) is primarily regulated by DPD. Inactivation of DPD using eniluracil is advantageous in that it renders 5-FU orally bioavailable with more predictable pharmacokinetics and blocks one of the major potential mechanisms of 5-FU chemoresistance. The purpose of this study was to initially document inactivation of DPD by eniluracil in primary and metastatic colorectal cancer (CRC) and then to assess the time-course of the regeneration of DPD activity in peripheral blood (and where possible, additional tissues). Methods: Of 28 patients entered, 23 were randomized to preoperative oral eniluracil (20 mg orally twice daily) or placebo prior to definitive resection of primary or metastatic CRC. Three patients were replaced, two because they had no residual tumor on pathologic evaluation and one for not taking the study drug. Patients received eniluracil 48, 36, 24 and approximately 12 h prior to surgical resection. In a second part of the study to document tissue regeneration of DPD, the additional five patients received eniluracil 144, 132, 120 and 108 h prior to surgical resection. DPD activity was measured in normal tissues, tumors and peripheral blood mononuclear cells (PBMC). Serum eniluracil and plasma uracil concentrations were determined before and through 28 days after eniluracil dosing. Data are presented as means ± SEM, and significance defined as P < 0.05. Results: Eniluracil inactivated DPD below the level of detection in primary and metastatic CRC as well as in normal tissues (0.0 pmol/min per mg protein) compared to primary tumor, metastatic tumor, PBMC, normal mucosa, and normal liver of patients receiving placebo (57 ± 12, 119 ± 19, 157 ± 22, 77 ± 12, 243 ± 24 pmol/min/ mg protein, respectively; P < 0.05). At the time of surgery, serum eniluracil and uracil concentrations were 207 ± 36 ng/ml and 2700 ± 170 ng/ml in drug-treated patients. Within 6 days following treatment with eniluracil, serum eniluracil and uracil concentrations were undetectable, while DPD activity in PBMC had returned to baseline. The second group of patients (n = 5) were given eniluracil 8 and 7 days prior to surgery to evaluate DPD regeneration in normal tissues and primary CRC tissue. In samples of these tissues, collected 6 days after the last eniluracil dose, DPD activity approached baseline in normal mucosa, normal liver and primary tumor (28 ± 12, 94 ± 23 and 20 ± 8 pmol/min per mg protein, respectively). Conclusions: These results demonstrate that oral administration of eniluracil inactivated DPD below the level of detection in normal tissues as well as in primary and metastatic CRC. After discontinuation of eniluracil, DPD rapidly returned toward baseline within 6 days in PBMC, normal intestinal mucosa and normal liver.

Original languageEnglish (US)
Pages (from-to)399-404
Number of pages6
JournalCancer chemotherapy and pharmacology
Volume52
Issue number5
DOIs
StatePublished - Nov 1 2003

Keywords

  • Colorectal cancer
  • Dihydropyrimidine dehydrogenase
  • Eniluracil

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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