UMLS:C0038362 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
8,852 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-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

Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.
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PMID:5-Fluorouracil prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer. 981 53

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues.
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PMID:Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model. 1003 74

In humans, 80-90% of an administered dose of 5-fluorouracil (5-FU) is degraded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate-limiting enzyme in pyrimidine catabolism. Cancer patients with decreased DPD activity are at increased risk for severe toxicity including diarrhea, stomatitis, mucositis, myelosuppression, neurotoxicity, and, in some cases, death. We now report the first known cancer patient who developed life-threatening complications after treatment with topical 5-FU and was shown subsequently to have profound DPD deficiency. RT-PCR and genomic PCR methodologies were used to identify a G to A mutation in the GT 5' splicing recognition sequence of intron 14, resulting in a 165-bp deletion (corresponding to exon 14) in this patient's DPD mRNA. Immunoprecipitation and Western blot analysis were then used to demonstrate that the aberrant DPD mRNA is translated into a nonfunctional DPD protein that is ubiquitinated. We conclude that the presence of this metabolic defect combined with topical 5-FU (a drug demonstrating a narrow therapeutic index) results in the unusual presentation of life-threatening toxicity after treatment with a topical drug. These data further suggest that degradation by the ubiquitin-proteosome-mediated system plays a role in the elimination of the DPD protein.
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PMID:Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. 1047 70

This study investigated the relationship among the pharmacokinetics of 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU); the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells; and treatment-related toxicity in 26 patients with surgically resected colorectal cancer treated with short daily infusions of 5-FU adjuvant chemotherapy, each cycle consisting of 5 consecutive days every 4 weeks. After the first chemotherapeutic cycle, severe stomatitis and diarrhea occurred in 5 patients and were related to the variations in the systemic disposition of the drug rather than to DPD activity. These patients showed a significant decrease in 5-FU clearance, and an increase in the 5-FU/5-FDHU area under the time-concentration curve (AUC) ratio, as compared with patients who experienced mild toxicities, whereas a low DPD activity was observed in only 2 patients. In conclusion, the results of this study demonstrate that the alterations in 5-FU and 5-FDHU pharmacokinetics are related to severe toxicities in patients treated with short intravenous infusion of 5-FU.
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PMID:Relationship between plasma concentrations of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil and toxicity of 5-fluorouracil infusions in cancer patients. 1235 29

Hand-foot syndrome (HFS) is a rare adverse reaction to oral fluoropyrimidine TS-1, which contains the dihydropyrimidine dehydrogenase (DPD) inhibitor. We treated a recurrent gastric cancer patient with chronic renal failure who developed grade 2 HFS, grade 2 conjunctivitis and grade 3 stomatitis soon after TS-1 administration. Those symptoms improved with the administration of vitamin B6, topical emollient therapy, and so on. We thought that the continuous elevation of serum 5-FU concentration, due to the accumulation of DPD inhibitor from the renal dysfunction, led to the development of HFS, although the participation of 5-FU metabolites such as F-beta-alanine cannot be ruled out.
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PMID:[A patient with recurrent gastric cancer who developed TS-1 induced hand-foot syndrome]. 1279 5

A dose-escalation study was conducted for patients with metastatic gastric cancer to determine the recommended dose of weekly intravenous (i.v.) cisplatin combined with a fixed dose of a new oral dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine, S-1, on an outpatient basis. Secondary endpoints were to define the toxicity profile and to determine tumour responses. S-1 was fixed at a dose of 70 mg/m(2)/day and was administered for 2 weeks followed by a 1-week rest. Three dose levels of cisplatin (10, 15 and 20 mg/m(2)) were studied. Cisplatin was infused over 30 min on days 1 and 8. 20 patients were enrolled. No dose-limiting toxicities (DLTs) were recorded during the administration of cisplatin up to 20 mg/m(2), except for grade 3 diarrhoea and stomatitis in one patient at dose level 3. No grade 4 adverse events occurred. However, grade 2 gastrointestinal adverse reactions, such as nausea and anorexia, were seen in 7 of 13 patients at dose level 3 within the first two treatment cycles. This was determined to be the maximum acceptable level that would not negate the advantages observed with use of an oral drug such as S-1. An objective tumour response was seen at all dose levels, and the overall response rate in the 18 patients evaluated was 61%. A higher response rate of 78% was observed in 9 patients who had received no prior chemotherapy. Oral S-1 with weekly cisplatin is a feasible and promising combination regimen that is appropriate for an outpatient setting. A randomised phase II study comparing this combination with S-1 alone in chemo-nai;ve patients is warranted.
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PMID:A phase I study of S-1 combined with weekly cisplatin for metastatic gastric cancer in an outpatient setting. 1455 24

Fluorouracil is used clinically against various solid tumours. Both fluorouracil toxicity and pharmacokinetics vary highly within and between individuals. The reasons why doses are not individualised routinely are difficulties in defining, predicting and achieving an optimal fluorouracil exposure or dose because of a narrow therapeutic index, nonlinear pharmacokinetics, variabilities in administration rates and metabolism, and in targets like thymidylate synthase. To individualise fluorouracil administration before the first dose, assessment of the individual dihydropyrimidine dehydrogenase (DPD) activity may be useful, because this genetically highly polymorphic enzyme controls approximately 80% of fluorouracil elimination. A complete or partial loss of DPD activity in 0.1 and 3-5% of Caucasians, respectively, leads to increased fluorouracil exposure and toxicity. Several methods to assess DPD activity in patients have been proposed (genotyping, various phenotyping methods), but each of them has limitations, as has the fluorouracil test dose approach. To adapt exposure towards fluorouracil a priori, a combination of genotyping and phenotyping may yield better prediction of toxicity than one method alone. A prerequisite for dose adaptation is the definition of fluorouracil exposure ranges with sufficient therapeutic activity, but without serious toxicity. While an increased risk of leukopenia, diarrhoea, stomatitis, and hand-foot syndrome during continuous 5-day infusions was related to fluorouracil exposures above an area under the plasma concentration-time curve (AUC) threshold of 25-30 mg.h/L, tumour response was higher when an AUC of approximately 30 mg.h/L was achieved, illustrating the extremely narrow therapeutic window of fluorouracil. Pharmacokinetic target values are less clear for other regimens, including chronomodulated regimens, which yielded a superior clinically efficacy and tolerability in several trials. However, the monitoring of fluorouracil plasma concentrations seems principally useful for individual a posteriori dose adjustment. Whether an adaptation of the fluorouracil starting dose to the results of two DPD activity tests before fluorouracil administration a priori, and the adaptation of doses to fluorouracil exposure a posteriori is a reasonable approach to better prevent toxicity and increase efficacy, remains to be evaluated in randomised clinical studies comparing these strategies to routine clinical safety monitoring.
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PMID:How may anticancer chemotherapy with fluorouracil be individualised? 1671 40

In the present article, we have summarized the phase I/II clinical trials on combination therapy of S-1 and docetaxel. With result of the phase I study, patients were treated with intravenous infusion of 40 mg/m2 docetaxel on day 1 and oral S-1 80 mg/m2/day on days 1 to 14 every 3 weeks. Forty eight patients received a total of 272 treatment cycles. No complete responses (CRs) and 27 partial responses (PRs) were observed for an overall response rate (CR+PR) of 56.2% (95% CI, 38-66%). Eighteen patients (37.5%) had stable disease (SD), and 3 patients (6.2%) had progressive disease (PD) as best response. The tumor control rate (CR+PR+SD) was 93.8% (95% CI, 83-98%). The median overall survival was 14.3 months (95% CI: 10.7-20.3 months) and the median time to tumor progression was 7.3 months (95% CI: 4.2-10.7 months). The most common grade 3-4 hematologic toxicities were neutropenia 58.3%, leukopenia 41.7%, febrile neutropenia 8.3%, and anemia 8.3%. The most common grade 3 nonhematologic toxicities were anorexia 14.6%, stomatitis 8.3%, nausea 6.3%, diarrhea 4.2%, constipation 4.2%, and vomiting 2.1%. No grade 4 nonhematologic toxicities were reported, and all treatment-related toxicities were resolved. The mechanisms underlying these synergistic effects of S-1 and docetaxel were examined by expression and activity analyses of 5-FU metabolic enzymes. The expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were decreased and that of orotate phosphorybosyl transferase (OPRT) was increased in mRNA, protein level and activity assay after the treatment with docetaxel and 5-FU in the TMK-1 gastric cancer cell. These findings strongly indicate that the combination chemotherapy of docetaxel and S-1 is effective against gastric carcinomas and therefore is a good candidate as a standard chemotherapeutic strategy in treating these tumors.
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PMID:[Combination chemotherapy of S-1 and docetaxel on advanced and recurrent gastric cancer]. 1689 78

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