Inhibiting 5-fluorouracil breakdown: a broken down approach to 5-fluorouracil modulation.

Attempts at enhancing the antitumor activity of 5-fluorouracil (5-FU) have traditionally focused on modulating the biochemical pathways that convert 5-FU to its phosphorylated metabolites or enhance the binding of these compounds to target enzymes or their incorporation into nucleic acids. Recent evidence suggests that modulation of the catabolic pathway for 5-FU may be at least as important in optimizing the effectiveness of fluoropyrimidine chemotherapy. Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the degradation of 5-FU. Overexpression of DPD in tumor cells is associated with relative 5-FU resistance due to rapid intracellular breakdown of the drug.1 DPD activity in the intestinal wall is responsible for the variable and erratic absorption of 5-FU, and hepatic DPD plays an important role in the rapid plasma clearance of intravenously administered 5-FU.2 It seems logical then that pharmacological inhibition of DPD could play a critical role in optimizing fluoropyrimidine therapy by enhancing oral absorption, decreasing plasma clearance, and circumventing a potentially important mechanism of drug resistance. Eniluracil is a mechanism-based, irreversible inactivator of DPD.3 In preclinical studies, a single oral dose of eniluracil inhibited more than 96% of DPD activity for up to 6 hours, and pretreatment with eniluracil increased the plasma half-life of 5-FU from 9 minutes to 100 minutes and produced 100% oral bioavailability.4 Thus, the combination of oral eniluracil with 5FU, administered daily, has the potential to simulate a protracted 5-FU infusion without the inconvenience and expense of indwelling venous catheters and infusion pumps. Eniluracil also augments the antitumor activity of 5FU in tumor-bearing animals, perhaps by preventing formation of 5-FU catabolites that may interfere with the antitumor activity of the drug.5 Two schedules of administration of eniluracil with 5-FU have been developed based on the results of phase I trials. Eniluracil and 5-FU can be administered orally for 5 days, repeated every 28 days, or the combination can be administered orally for 28 consecutive days followed by a 1-week rest.6,7 Bone marrow suppression is the dose-limiting toxicity of the 5-day schedule, while diarrhea is the dose-limiting toxicity of the 28-day schedule. The employed doses of eniluracil have been shown to completely suppress DPD activity in peripheral-blood mononuclear cells for at least 24 hours, to markedly prolong the plasma half-life of 5-FU, and to suppress the formation of 5-FU catabolites. Indeed, eniluracil changes the elimination of 5-FU from primarily catabolism to primarily renal elimination of the unchanged drug.8 As might be expected, the tolerable doses of 5FU are markedly reduced when given with eniluracil compared with standard regimens, and care must be taken not to expose patients to standard doses of 5FU within 60 days of treatment with eniluracil, because unacceptably severe toxicity might result. In this issue of Clinical Colorectal Cancer, Marsh and colleagues report the results of a phase II trial of the 28-day schedule of eniluracil plus 5FU conducted by the Eastern Cooperative Oncology Group in patients with metastatic colorectal cancer.9 The doses employed are 15% lower than those finally chosen for the pivotal randomized trials of this regimen in metastatic colorectal cancer. While the regimen was well tolerated, only modest antitumor activity was observed (13.2% objective response rate in previously untreated patients, median progression-free survival of 3.4 months, and median overall survival of 11.1 months). Since completion of this study, the results of 2 prospective randomized trials comparing the 28-day eniluracil/5-FU regimen to intravenous administration of 5FU/leucovorin (LV) (daily times 5, every 28 days) as first-line therapy for metastatic colorectal cancer have been reported. In the pivotal North American trial, 981 patients were randomized and 964 patients were treated.10 Median duration of survival was 13.3 months in the eniluracil/5-FU group and 14.5 months in the 5-FU/LV group. While not statistically inferior, these results failed to meet the protocol-specified definition of equivalence with the standard regimen. Median duration of progression-free survival for eniluracil/5FU was statistically inferior to control (5.0 months vs. 5.5 months) although objective rates of tumor response were nearly identical in the 2 treatment groups (12.2% for eniluracil/5-FU and 12.7% for 5-FU/LV). In a second randomized trial of similar design conducted in Western Europe and Australia/New Zealand, the patients who received eniluracil/5-FU had a statistically inferior survival compared to those treated with 5