UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Ethynyluracil (5-EU; 776C85) is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase that improves the antitumor activity of 5-fluorouracil (5-FU) to a greater extent than can be accounted for by the improved 5-FU pharmacokinetics that result from preventing the catabolism of 5-FU. We therefore tested the effects of (R)-5-fluoro-5,6-dihydrouracil (5-FUH2), the 5-FU catabolite extensively formed in the absence of 5-EU, on the antitumor activity and toxicity of 5-FU in 5-EU-treated rats bearing large s.c. tumors. Rats were dosed once weekly for 3 weeks with the following regimens: 100 mg/kg 5-FU (maximum tolerated dose), 10 mg/kg 5-FU 1 h after 1 mg/kg 5-EU, or 10 mg/kg 5-FU plus 90 mg/kg 5-FUH2 1 h after 1 mg/kg 5-EU. The latter regimen was designed to approximate the exposure produced from 5-FU in the absence of 5-EU, where > 80% of the dose is catabolized. 5-FU produced complete and sustained tumor regressions in 94% of the animals pretreated with 5-EU. In contrast, 5-FU in combination with 5-FUH2 produced complete regression in only 38% of the 5-EU-treated rats, which was similar to the antitumor activity of 5-FU in the absence of 5-EU. All treatments resulted in 7-11% transient weight loss. 5-FU produced no other notable toxicity in 5-EU-treated rats. However, 5-FUH2 added to this regimen caused transient diarrhea and stomatitis in 13% of the animals, which was similar to the toxicity produced by 5-FU in the absence of 5-EU. Thus, 5-FUH2, or other downstream catabolites of 5-FU, impaired the antitumor activity and slightly increased the toxicity of 5-FU. Accordingly, 5-EU approved to improve the efficacy of 5-FU by preventing the formation of 5-FU catabolites.
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PMID:Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil. 788 16

5-Benzyloxybenzyluracil (BBU) is the most potent inhibitor (Ki approximately 30 nM) of dihydrouracil dehydrogenase (EC 1.3.1.2), the first enzyme in the catabolic pathway of pyrimidine bases and their analogues, including 5-fluorouracil (FUra). The effect of BBU on modulating the chemotherapeutic efficacy and host toxicity of FUra was evaluated using human colon carcinoma DLD-1 grown in culture and as xenografts in anti-thymocyte serum (ATS)-immunosuppressed mice. The effect of BBU on FUra-induced host toxicity was also studied in nontumor-bearing-ATS-immunosuppressed and immunocompetent mice. At 0.2 microM, BBU potentiated growth inhibition by FUra of DLD-1 cells in culture (the concentration that produces 50% inhibition of cell growth was 0.48 microM at 3 h) by 1.3-fold (from 45 to 28% growth). BBU also enhanced the cytocidal effect of FUra (0.48 microM, 3 h) against DLD-1 grown in soft agar by 3-fold (from 45 to 15% growth). In ATS-immunosuppressed mice bearing DLD-1 xenografts, coadministration of BBU with FUra enhanced not only the efficacy of FUra in killing the tumor but also protected the host from FUra-induced host toxicity. This was particularly evident at low doses of FUra. Coadministration of BBU (10 mg/kg/day x 2) with FUra at 30 mg/kg/day x 2 reduced tumor weight by 16-fold (from 799 to 49 mg) and increased host survival from 83 to 100%. The enhancement of tumor kill and protection from host toxicity induced by FUra was also evident at higher doses of FUra, albeit to a lesser degree. At 120 mg/kg/day x 2 FUra, coadministration of BBU (10 mg/kg/day x 2) reduced tumor weight from 44 to 10 mg and increased survival of the animals from 33 to 50%. Host protection from FUra-induced toxicity was corroborated further by the protective effect of BBU, inferred from the increase in the dose that produces 50% mortality in ATS-immunosuppressed (from 135 to 195 mg/kg/day x 2) and immunocompetent (from 250 to 300 mg/kg/day x 2) mice. Therefore, coadministration of BBU improved the therapeutic index of FUra by 5.5-fold (from 2.3 to 12.6) as a result of potentiating the antitumor efficacy of FUra and reducing its induced host toxicity. This protection by BBU sharply contrasts with the effect of most other dihydrouracil dehydrogenase inhibitors, which at therapeutic doses increase host toxicity by FUra. These findings may lead to a more successful use of FUra in cancer chemotherapy.
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PMID:Potentiation of 5-fluorouracil efficacy by the dihydrouracil dehydrogenase inhibitor, 5-benzyloxybenzyluracil. 792 35

5FU tends to be used more and more frequently; this fact can be explained by its modulation, mainly by folinic acid. Pharmacokinetic follow-up of 5FU with dose adaptation has demonstrated its clinical usefulness by reducing significantly drug side-effects without any impairment in tumor response. Whatever the anticancer drug considered, it is theoretically possible to predict individual capacities for clearing it. This possibility has been explored for 5FU. Among the different tested variables only gender has a determined influence with females showing an average 15% reduction in 5FU clearance as compared to males. Age, hepatic function, nutritional status have no clear influence on 5FU clearance. 5FU catabolism is governed by a key enzymatic step involving dihydropyrimidine dehydrogenase (DPD). Recent case reports have shown that patients with partial or total DPD deficiency shown in lymphocytes were exhibiting severe 5FU related toxicities. A positive and significant correlation has been established between 5FU clearance and DPD activity measured in lymphocytes. This correlation is too weak for allowing individual 5FU dose to be calculated on the basis of lymphocyte DPD activity. Nevertheless DPD determination may allow high risk patients, with partial or total DPD deficiency to be identified.
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PMID:[Evolution from pharmacokinetics to pharmacogenetics. The example of 5-fluorouracil]. 805 51

5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimidine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FUra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcinoma. Two schedules were studied: (a) FUra daily for 4 days i.v. push (daily x 4); and (b) FUra administered i.v. push weekly for 3 weeks (weekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 mg/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra alone and for FUra in combination with EU. Although EU was not toxic and not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was schedule dependent, yielding 13% complete and sustained tumor regression on the weekly schedule and no complete and sustained tumor regression on the daily schedule. The combination of FUra and EU produced 100% complete and sustained tumor regression on both schedules. The therapeutic index was < or = 1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(phosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(phosphonacetyl)-L-aspartate induced minimum improvements on the daily schedule and only increased the therapeutic index to 1.5 on the weekly schedule. Because a 4-day continuous infusion of FUra alone at the maximum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.
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PMID:5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. 813 56

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.
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PMID:3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase. 813 51

5-Ethynyluracil (5-EU, 776C85) is a mechanism-based irreversible inhibitor of dihydropyrimidine dehydrogenase (EC 1.3.1.2), the rate-determining enzyme in 5-fluorouracil (5-FU) catabolism. In the present study, 5-EU was found to be a potent modulator of 5-FU catabolism in mice and rats. Liver extracts prepared up to 6 hr after a 5-EU dose (2 mg/kg) were > 96% inhibited in their ability to catalyze 5-FU degradation. 5-EU treatment increased the elimination t1/2 and the area under the plasma concentration-time curve of 5-FU. 5-FU oral bioavailability was approximately 100% in rats pretreated with 5-EU. Consequently, 5-EU induced a linear relationship between the area under the plasma concentration-time curve and the oral dose of 5-FU. As expected from the preservation of plasma 5-FU, 5-EU potentiated the antitumor activity and the toxicity of 5-FU in two mouse tumor models (Colon 38 and MOPC-315). However, 5-EU potentiated the antitumor activity to a greater degree and thereby increased the therapeutic index of 5-FU 2- to 4-fold.
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PMID:5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. 824 11

We studied the effects of 5-ethynyluracil (776C85 and 776C), a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase, on the antitumor efficacy and pharmacokinetics of tegafur (FT), a prodrug of 5-fluorouracil (5-FU), in rats with large s.c. colon carcinoma. Rats were dosed p.o. once daily for 7 days with either FT, FT and uracil in a 1:4 molar ratio (UFT), FT 1 h after 776C (776C/FT), or UFT 1 h after 776C (776C/UFT). 776C, which was dosed at 1 mg/kg, had neither intrinsic antitumor activity nor toxicity. The rank order in antitumor efficacy at the maximal tolerated dose of the FT (mg/kg/day) component was 776C/FT (5 mg/kg/day) > or = UFT (80 mg/kg/day) = 776C/UFT (5 mg/kg/day) >> FT (200 mg/kg/day). One-hundred % of rats treated with 776C/FT had complete and sustained tumor regression with no severe toxicity. The area under the plasma 5-FU concentration versus the time curve generated from UFT, FT, and 776C/FT at their maximum tolerated dose was 140, 50, and 27 microM.h, respectively. The area under the concentration in plasma versus time curve did not correlate with the rank order of antitumor efficacy. The vast majority of 5-FU derived from FT (alone) appeared to be rapidly catabolized. Furthermore, plasma exposure of 5-FU derived from UFT was more variable than that from 776C/FT. Each therapy also produced different levels of plasma uracil. Endogenous plasma uracil levels (1-3 microM) were not affected by FT but increased to 100 microM after dosing with 776C. Plasma uracil from UFT was 800 microM 1 h after dosing. These results suggest that moderately elevated uracil (776C/FT) may be beneficial, whereas uracil that is greatly elevated during the first 5 h (UFT) and 5-FU catabolites (FT alone) may interfere with antitumor efficacy. 776C, coadministered with FT, could provide once-a-day oral therapy for cancer patients.
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PMID:5-Ethynyluracil (776C85): effects on the antitumor activity and pharmacokinetics of tegafur, a prodrug of 5-fluorouracil. 852 18

5-Fluorouracil (FU) is metabolized by dihydropyrimidine dehydrogenase (DPD). Patients with suspected or proven DPD deficiency develop more or less severe FU-related side effects including death. In these reported cases, DPD activity in peripheral blood mononuclear cells (PBMC-DPD) was < 100 pmol/min/mg protein. A circadian rhythm in PBMC-DPD activity has been observed, with a peak at 1 a.m. and a trough at 1 p.m. on average. As a corollary, a circadian rhythm was observed in FU plasma concentration, with a peak at 11 a.m. and a trough at 11 p.m. on average. A significant relationship between PBMC-DPD activity and FU clearance was established but the link was weak (r = 0.31). Thus, a FU dose adaptation based on PBMC-DPD is not justified whereas a pharmacokinetically based FU dose adaptation is recommended. Experimental studies have shown that DPD activity in tumor cell lines is related to FU cytotoxicity. Although resistance to FU depends on many factors, recent clinical studies in head and neck cancer patients treated by FU suggest that tumoral DPD activity is a determining factor in predicting FU-responsiveness.
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PMID:Individualizing therapy with 5-fluorouracil related to dihydropyrimidine dehydrogenase: theory and limits. 885 47

We have focused our attention on the development of a novel form of a tegafur-based [FT; a prodrug of 5-fluorouracil (5-FU)] antitumor agent. We have used two biochemical and pharmacological modulators of 5-FU to improve its overall activity. To potentiate the antitumor activity of FT, 5-chloro-2,4-dihydroxypyridine (CDHP) was used as a potent reversible inhibitor of 5-FU degradation. The reduction of gastrointestinal (GI) toxicity, induced in the host by 5-FU, was modulated by potassium oxonate (Oxo), an inhibitor of orotate phosphoribosyltransferase that catalyzes the phosphorylation of 5-FU, a process believed to be responsible for the toxic effects of 5-FU. When CDHP and FT were simultaneously given orally to Yoshida sarcoma-bearing rats in various molar ratios, the antitumor effect of FT was significantly potentiated by the combination consisting of at least a 0.2 versus 1 molar ratio of CDHP to FT, respectively. This augmentation of an antitumor activity was supported by potent and prolonged inhibition of dihydrouracil dehydrogenase activity (5-FU degrading activities) in the liver of tumor-bearing rats after oral CDHP (0.2:0.8 molar ratio) and furthermore by elevation and over 12 h retention of 5-FU levels in the tumors following combined administration of FT and CDHP at a molar ratio of 1:0.4, respectively. Moreover, to reduce the severe GI injury and subsequent loss of body weight, observed in parallel with an increased antitumor efficacy, Oxo was given orally to Yoshida sarcoma-bearing rats and nude rats xenografted with H-81 human gastric carcinoma, during consecutive administration of the FT-CDHP mixture. Combined treatment with Oxo and FT (1:2 molar ratio) supplemented with 0.4 molar CDHP resulted in protection of body weight loss without affecting the high antitumor efficacy of the FT-CDHP mixture. When [2-14C]FT plus CDHP was administered with Oxo, the 14C-labeled fluoronucleotide content was objectively decreased in the GI tract of the tumor-bearing rats but not in the tumor and bone marrow, which supports our initial hypothesis. Based on these promising data, we propose a suitable formulation of a FT-based anticancer drug, called S-1, and consisting of FT, CDHP and Oxo at a 1:0.4:1 molar ratio and showing tumor-selective cytotoxicity of 5-FU.
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PMID:Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. 886 23

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FUra) selectively in tumors through the intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine). 5'-dFUrd is metabolized to 5-FUra by thymidine phosphorylase (dThdPase) located in high levels in various types of solid tumors from patients, whereas 5-FUra generated is catabolized to dihydrofluorouracil by dihydropyrimidine dehydrogenase (DPD). The present study investigated whether the efficacy of capecitabine and its intermediate metabolite 5'-dFUrd correlates with levels of these enzymes in various human cancer xenograft models. Capecitabine and 5'-dFUrd were highly effective and inhibited tumor growth by more than 50% in 18 of 24 xenograft lines (75%) and 15 of 24 xenograft lines (63%), respectively, whereas 5-FUra and a mixture of tegafur and uracil were effective only in 1 of 24 (4.2%) and 5 of 24 (21%), respectively. The efficacy of capecitabine correlated with dThdPase activity. However, capecitabine was effective even in tumors with lower levels of dThdPase if DPD levels were also lower. In contrast, it was not as effective even in tumors with sufficient levels of dThdPase if DPD levels were very high. The efficacy of capecitabine consequently correlated very well with and depended on the ratio of these two enzymes in tumors. These results indicate that capecitabine might exert its efficacy through 5-FUra generated in tumor tissues but not through that generated in normal organs. On the other hand, there was no correlation between the efficacy of a mixture of tegafur and uracil and these enzyme activities in tumors. The efficacy of capecitabine would be optimized by selecting patients who have tumors with a high ratio of dThdPase to DPD activities.
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PMID:Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. 948 21

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