5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil.

Baccanari, David P.; Davis, Stephen T.; Knick, Victoria B.; Spector, Thomas

doi:10.1073/pnas.90.23.11064

Cited by 111 publications

(48 citation statements)

References 23 publications

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“…Rat livers were thus > 96% inhibited in their ability to catalyse 5-FU degradation. This result is in complete agreement with the study of Baccanari et al (1993), which reported the same extent of inhibition when DPD activity was measured in liver extracts prepared 1 h or 6 h after rats were treated with a single dose of GW776 (2 mg kg-' p.o.). GW776 led to a decrease in FBAL formation by a factor of-I 10, whereas F formation decreased by a factor of only -10 (Table 3).…”

Section: Proportions Of 5-fu and Its Metabolitessupporting

confidence: 92%

“…GW776 increases the therapeutic index of 5-FU in mouse (Baccanari et al, 1993) and rat (Table 3). No 5-FU incorporated into RNA was observed in the experiments with 5-FU alone whereas the incorporation of 5-FU into RNA, detected as 2'-and 3'FUMP, was low (0.1% of the injected dose) but detectable in the experiments with 5-FU + GW776 (Table 3).…”

Section: Proportions Of 5-fu and Its Metabolitesmentioning

confidence: 98%

“…The combination of GW776 and 5-FU has great clinical potential. GW776 increases the half-life of 5-FU from approximately 14 min to approximately 5 h in humans (Khor et al, 1996) and thereby enables oral dosing to replace the 5-day bolus and the protracted continuous infusion schedules (Baccanari et al, 1993). Moreover, the dry powder of orally formulated 5-FU presents the advantage of being devoid of cardiotoxic breakdown products found in i.v.…”

Section: Proportions Of 5-fu and Its Metabolitesmentioning

confidence: 99%

“…5-Ethynyluracil (GW776) is a potent inactivator of the catabolic pathway of 5-FU acting on dihydropyrimidine dehydrogenase (DPD), the enzyme that converts 5-FU into its first catabolite, 5,6-dihydro-5-fluorouracil (FUH2), thereby preserving 5-FU from its rapid and extensive catabolism (Porter et al, 1992;Baccanari et al, 1993;Spector et al, 1993). Increases in the 5-FU half-life and in the renal elimination of unchanged 5-FU were recently reported in cancer patients (Khor et al, 1996).…”

mentioning

confidence: 99%

“…Increases in the 5-FU half-life and in the renal elimination of unchanged 5-FU were recently reported in cancer patients (Khor et al, 1996). GW776 greatly improved the anti-tumour efficacy, the oral bioavailability and the therapeutic index of 5-FU in animals (Baccanari et al, 1993;Cao et al, 1994). Moreover, Davis et al (1994) demonstrated that GW776 protected dogs from 5-FU-induced neurotoxicity that could be due to FAC (Koenig and Patel, 1970;Okeda et al, 1984Okeda et al, , 1990.…”

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confidence: 99%

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5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Arellano

Mc²,

Martino³

et al. 1997

Br J Cancer

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Summary We studied the effects of 5-ethynyluracil (GW776), a potent inactivator of dihydropyrimidine dehydrogenase, on the metabolism of 5-fluorouracil (5-FU), in particular with respect to formation of the toxic compounds fluoroacetate (FAC) and 2-fluoro-3-hydroxypropionic acid (FHPA), using fluorine-19 nuclear magnetic resonance and the isolated perfused rat liver model. Livers were perfused with 5-FU alone at a dose of 15 mg kg-' body weight or with 5-FU + GW776 at doses of 15 mg 5-FU kg-' body weight and 0.5 mg GW776 kg-' body weight injected 1 h before 5-FU. All 5-FU was metabolized in experiments with 5-FU alone whereas unmetabolized 5-FU represented 94% of the fluorinated compounds measured in experiments with 5-FU + GW776. GW776 modulated both the catabolic and the anabolic pathways of 5-FU, the most striking effect being on the degradative pathway. The amount of 5-FU catabolites decreased by a factor of 27 in the presence of GW776. The modulator led to a decrease in a-fluoro-3-alanine (FBAL) formation by a factor of approximately 110, while fluoride ion formation decreased by a factor of approximately 10. By strongly lowering the metabolism of 5-FU into FBAL, GW776 circumvented the transformation of FBAL into toxic FAC and FHPA. 5-FU anabolites increased by a factor of approximately 7 in the presence of GW776. The level of free fluoronucleotides and 5-fluorouridine-5'-diphosphate sugars was increased up to fivefold. No incorporation of 5-FU into RNA could be measured in experiments with 5-FU alone whereas, although low (0.1% of 5-FU injected dose), it was detectable in experiments with 5-FU + GW776. These results suggest that GW776 may be useful for attenuating the not very common but serious cardiotoxic and/or neurotoxic side-effects of 5-FU that are probably due to FBAL metabolites.Keywords: 5-fluorouracil; 5-ethynyluracil (GW776); 19F nuclear magnetic resonance; modulation of 5-fluorouracil metabolism; fluoroacetate; 2-fluoro-3-hydroxypropionic acid; isolated perfused rat liver 5-Fluorouracil (5-FU) is one of the most commonly used anticancer agents for treatment of solid tumours. Common clinical adverse reactions include myelosuppression, diarrhoea, vomiting and mucositis. Over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to 5-FU has rapidly increased (Anand, 1994;Yeh and Cheng, 1994; and references cited therein). The biochemical mechanism underlying these toxic side-effects remains unclear, although it has been postulated that 5-FU, and more precisely its main catabolite ex-fluoro-p-alanine (FBAL) (Mukherjee and Heidelberger, 1960;Bemadou et al, 1985; Heggie et al, 1987; Hull et al, 1988), might be transformed into fluoroacetate (FAC) (Koenig and Patel, 1970), a highly cardiotoxic and neurotoxic poison (Pattison and Peters, 1966). We demonstrated on the isolated perfused rabbit heart model that commercial solutions of 5-FU contain cardiotoxic impurities, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), that are derived from...

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Section: Proportions Of 5-fu and Its Metabolitessupporting

confidence: 92%

Section: Proportions Of 5-fu and Its Metabolitesmentioning

confidence: 98%

Section: Proportions Of 5-fu and Its Metabolitesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Arellano

Mc²,

Martino³

et al. 1997

Br J Cancer

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New drugs in the treatment of colorectal carcinoma

Punt¹

1998

Cancer

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BACKGROUND Treatment with 5‐fluorouracil (5‐FU) plus leucovorin has been the unofficial standard therapy for patients with colorectal carcinoma (CRC) for more than a decade; however, the optimal dose and schedule remain a matter of debate. Recently several new drugs have shown activity in this disease. These include irinotecan (CPT‐11); oxaliplatin; the thymidylate synthase inhibitors raltitrexed, uracil/tegafur (UFT), capecitabine, and S‐1; the biochemical modulators trimetrexate and 5‐ethynyluracil; and the monoclonal antibody 17‐1A. METHODS The results of clinical trials with these and other new agents, as well as their current status and main characteristics, were reviewed. RESULTS Several of these agents, some with a novel mechanism of action, show promising activity in CRC. In combination with 5‐FU and leucovorin, trimetrexate showed encouraging response rates in Phase II studies. Other interesting agents include capecitabine, UFT, and S‐1. The biochemical modulator 5‐ethynyluracil may allow the oral administration of 5‐FU; however, results of Phase II clinical trials are not yet available. CPT‐11 is in the most advanced stage of development and, based on consistent data generated in extensive Phase II studies, currently appears to be a reasonable choice for 5‐FU‐resistant or refractory disease. Another promising agent is oxaliplatin, which showed activity as first‐line and second‐line treatment. CONCLUSIONS Several new agents have shown promise in the treatment of CRC, and changes in the standard treatment of advanced or high risk CRC appear likely in the near future. Cancer 1998;83:679‐689. © 1998 American Cancer Society.

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Non-invasive19F-NMRS of 5-fluorouracil in pharmacokinetics and pharmacodynamic studies

1998

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Knowledge of the exact dose and rate at which an antitumor agent is delivered to its target site is postulated to be crucial to proper patient management. It is now possible to obtain such information using non‐invasive 19F‐NMRS (nuclear magnetic resonance spectroscopy) following the administration of 5‐fluorouracil (5‐FU). We have performed such studies in 103 patients with breast, colorectal and other tumors. Measurable 19F signals were detected in 99 of these patients (92.5%). Estimation of the tumoral t1/2 of 5‐FU in these patients revealed that 51 of them (51.5%) exhibited a tumoral t1/2 greater than 20 min, a value we had characterized as indicating drug trapping in the tumor. Of these patients, 46 who received regimen bolus 5‐FU 600 mg/m2 with leucovorin for their treatment have been evaluated. In these patients, the association between trapping and response remains very high (p < .000001). None of the non‐trappers responded to chemotherapy, whereas 70% of the evaluable trappers responded. Details are presented here on the methodology of NMRS data acquisition and on their pharmacokinetic analysis. The potential mechanisms underlying the trapping effect appear to be predicated primarily on transport processes. Suggestions are presented on how such pharmacokinetic imaging studies may extend both our understanding of the mechanism of action of 5‐FU, and how they could be used to optimize patient treatment. © 1998 John Wiley & Sons, Ltd.

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5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil.

Cited by 111 publications

References 23 publications

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

New drugs in the treatment of colorectal carcinoma

Non-invasive19F-NMRS of 5-fluorouracil in pharmacokinetics and pharmacodynamic studies

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