Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors.
OBJECTIVE
To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity.


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 micromol/L before therapy to 27.76 micromol/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.


CONCLUSIONS
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 at 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.
Ahmed
F Y
FY
Departments of Medicine and Therapeutics and Pathology, Institute of Medical Sciences, University of Aberdeen, and Department of Surgery, Aberdeen Royal Infirmary, Aberdeen.
Johnston
S J
SJ
Cassidy
J
J
O'Kelly
T
T
Binnie
N
N
Murray
G I
GI
van Gennip
A H
AH
Abeling
N G
NG
Knight
S
S
McLeod
H L
HL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D000284:Administration, Oral; D000368:Aged; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D042943:Dihydrouracil Dehydrogenase (NADP); D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D011300:Preoperative Care; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)