Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer

Mani, Sridhar; Hochster, Howard S.; Beck, Thomas M.; Chevlen, Eric; O’Rourke, Mark Allen; Weaver, Charles H.; Bell, William N.; White, Robin; McGuirt, Chip; Levin, Jeremey; Hohneker, John; Schilsky, Richard L.; Lokich, Jacob J.

doi:10.1200/jco.2000.18.15.2894

Cited by 41 publications

(19 citation statements)

References 24 publications

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“…Our findings, similar to these results, suggested that most of 5-FU within insensitive tumor cells was quickly catabolized by a higher DPD level, which regulated the amount of 5-FU available for anabolism, thereby affecting its cytotoxicity. In addition, these results suggested that DPD inhibitors, such as eniluracil [30] , uracil [31] , 5-chloro-2,4-dihydroxypyrimidine (CDHP) [32] , and BOF-A2 [33] , might be used as a novel type of biochemical modulators for elevating the antitumor activity of 5-FU. It has been indicated in our work that TS may contribute greatly to the sensitivity of FdUrd, and the higher the TS mRNA levels, the higher the IC50 of FdUrd.…”

Section: Discussionmentioning

confidence: 99%

Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2’-deoxyuridine

Ma¹,

Zhu²,

Ji³

et al. 2004

WJG

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AIM:To determine the expression levels of three metabolic enzymes of fluoropyrimidines: thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in seven human gastrointestinal cancer cell lines, and to compare the enzyme levels with the sensitivity to 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd). METHODS:TS, TP and DPD mRNA levels were assessed by semi-quantitative RT-PCR, TP and DPD protein contents were measured by ELISA. Fifty percent inhibitory concentrations of growth (IC50), representing the sensitivity to drugs, were determined by MTT assay. RESULTS: IC50 values ranged from 1.28 to 12.26 uM for 5-FU, and from 5.02 to 24.21 uM for FdUrd, respectively. Cell lines with lower DPD mRNA and protein levels tended to be more sensitive to 5-FU (P<0.05), but neither TS nor TP correlated with 5-FU IC50 (P>0.05). Only TS mRNA level was sharply related with FdUrd sensitivity (P<0.05), but TP and DPD were not (P>0.05). A correlation was found between mRNA and protein levels of DPD (P<0.05), but not TP (P<0.05).CONCLUSION: DPD and TS enzyme levels may be useful indicators in predicting the antitumor activity of 5-FU or FdUrd, respectively.

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Section: Discussionmentioning

confidence: 99%

Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2’-deoxyuridine

Ma¹,

Zhu²,

Ji³

et al. 2004

WJG

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“…In addition, HFS occurred in 9 -10% in European phase II trial; however, most of the cases were limited to grade 1 -2 (Chollet et al, 2003;Van den Brande et al, 2003). Interestingly, a low incidence of HFS has also been reported for eniluracil, an irreversible DPD inhibitor, plus oral 5-FU (Mani et al, 2000). Only two of 55 patients (4%) treated with oral 5-FU plus eniluracil had mild HFS.…”

Section: Discussionmentioning

confidence: 99%

Plasma concentrations of 5-fluorouracil and F-β-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil

et al. 2003

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The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg m À2 day À1 for 5 days. After a washout period of 9 days, the patients received two divided doses daily for 28 days. S-1 was administered orally at about 0900 and 1900 hours. The daily dose of S-1 in terms of tegafur was 80 mg day À1 in patients with a body surface area (BSA) of o1.25 m 2 , 100 mg day À1 in those with a BSA of X1.25 m 2 to o1.5 m 2 , and 120 mg day Continuous protracted intravenous infusion (PVI) of 5-fluorouracil (5-FU) has a higher response rate, less frequent haematologic toxicity (mainly neutropenia), and more frequent hand -foot syndrome (HFS) than bolus injection of 5-FU in patients with metastatic colorectal cancer (The Meta-Analysis Group in Cancer, 1998). Hand -foot syndrome and stomatitis each occur in about 23% of patients given 5-FU by PVI, whereas grade 3 leukopenia develops in only 1%. Most patients who receive 5-FU by PVI have no severe toxicity; the dose-limiting toxicity (DLT) is HFS (Lokich et al, 1989). Previous clinical trials have shown that PVI of 5-FU is one of the most effective and safest regimens. However, PVI requires a central venous catheter as well as an ambulatory pump, which is expensive and may lead to complications, and adversely affect patients' quality of life. Oral fluoropyrimidine derivatives have been developed to circumvent the problems associated with PVI of 5-FU. S-1 is one such derivative that combines tegafur with two modulators of 5-FU metabolism, 5-chloro-2,4-dihydroxypyridine (CDHP), a reversible inhibitor of dihydropyrimidine dehydrogenase (DPD), and potassium oxonate, in a molar ratio of 1 : 0.4 : 1. Tegafur, an oral prodrug of 5-FU, is gradually converted to 5-FU and rapidly metabolised by DPD in the liver. The DPD-inhibitory activity of CDHP is 180-fold higher than that of uracil, confirmed to be an effective DPD inhibitor in the form of uracil/tegafur (UFT) in vitro. Potassium oxonate is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases the incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea.F-b-alanine (FBAL) is a main metabolite of 5-FU. F-b-alanine and fluorocitrate are thought to cause the cardiotoxic and neurotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Koenig and Patel, 1970;Okeda et al, 1990;Robben et al, 1993;Diasio, 1998;Kuwata et al, 2000;Kato et al, 2001). The CDHP component of S-1 inhibits DPD, the rate-limiting enzyme in the catabolic pathway of 5-FU. Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after PVI of 5-FU. However, information on plasma FBAL concentrations in patients given 5-FU remains scant...

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“…Phase II trials with 33, 106, and 84 breast cancer patients reported grade 1 or grade 2 HFS at a rate of 15%, 5%, and 2%, respectively (43,45,46). Similarly, 2 of 55 (4%) colorectal cancer patients and <5% of 45 hepatocellular cancer patients reported mild HFS in phase II studies (11,44). Despite an improved safety profile, further research was abandoned after two large phase III trials suggested 5-FU/ eniluracil had inferior efficacy compared with 5-FU/leucovorin (66,67).…”

Section: Dpd Inhibitors and Hfsmentioning

confidence: 99%

Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines?

Yen-Revollo

Goldberg

McLeod

2008

Clinical Cancer Research

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Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil (5-FU) delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption, dosage reduction, or, even, therapy discontinuation for patients on a capecitabine regimen. Interestingly, addition of a dihydropyrimidine dehydrogenase (DPD) inhibitor, such as uracil, 5-chloro-2,4-dihydroxypyridine, or eniluracil, to the fluoropyrimidine treatment regimen significantly diminishes the incidence of HFS. DPD inhibitors were initially combined with fluoropyrimidines to increase the efficacy of the drugs by impairing the DPDmediated catabolism of 5-FU. However, with the accumulating findings from clinical trials that show the benefits of DPD inhibition on decreasing the risk of HFS, consideration should be given to changing the recommendations for the treatment of cancer patients with fluoropyrimidines to include DPD inhibitor components as standard therapy.

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Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer

Abstract: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.

Cited by 41 publications

References 24 publications

Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2’-deoxyuridine

Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2’-deoxyuridine

Plasma concentrations of 5-fluorouracil and F-β-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil

Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines?

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