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)

Leucovorin (LV), given intravenously the orally becomes 5, 10-methylene tetrahydrofolate in both cancer and normal cells. FdUMP which is an active metabolite of 5-FU binds tightly to thymidylate synthase in the presence of the cofactor 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Clinically, the combination of LV and 5-FU is given parenterally by two schedules; 5 consecutive days schedule and weekly schedule. Five 5 consecutive days-schedule is divided into 2 methods. One is a 200 mg/m2/day of LV by Machover, and the other is 20 mg/m2/day of LV by O'Connell. The weekly schedule is a 2-hour infusion of dl-LV (500 mg/m2) and iv bolus of 5-FU (600 mg/m2), given 1 hour after the beginning of LV infusion by Petrelli. A multicenter cooperative study in Japan was conducted to evaluate the clinical efficacy of LV and 5-FU using the weekly schedule by Petrelli. Response rates were 31.5% and 41.2% against advanced gastric and colorectal cancer respectively. Then, we carried out a randomized early phase II study using 250 mg/m2 of l-LV weekly (similar to the schedule of Petrelli's, armA) and 100 mg/m2 (similar to the schedule of Machover's, arm B) or 10 mg/m2 (similar to the schedule of O'Connell's, arm C) of l-LV for 5 consecutive days against gastric cancer. The response rate was 33.3% in arm A, 24.1% in arm B and no response in arm C. Toxicity was within acceptable limits, Toxic effects included diarrhea, stomatitis, anorexia and myelohypoplasia. Our data suggests that high-dose LV and 5-FU seems to be a very promising combination but, there was no responder using low dose (10 mg/m2) of l-LV schedule against gastric cancer patients.
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PMID:[High-dose leucovorin and 5-FU]. 162 51

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).
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PMID:Phase I study of high dose 5-fluorouracil and high dose Leucovorin with low dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies. 173 89

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.
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PMID:Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. 187 24

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.
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PMID:Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group. 189 77

Sixteen patients with metastatic carcinoma of the colon were treated with a regimen of leucovorin 200 mg/m2, given as a 10-min infusion followed by a median dose of 833 mg/m2 (range 500-1000 mg/m2) 5-fluorouracil every two weeks. For the 16 patients with proven metastatic disease, two-year survival exceeds 50%. Responses were: 2 complete; 4 partial; 4 minor; 3 progression; and 3 not evaluable but without progression to date. Toxicities include: 8 (50%) leukopenia; 9 (56%), 1 severe thrombocytopenia; 9 (56%), 2 severe, diarrhea; 9 (56%), 3 severe, nausea/vomiting; 8 (50%), 1 severe, stomatitis; 7 (44%) conjunctivitis; 6 (38%) alopecia; and 13 (81%), 3 severe, neurotoxicity. Leucovorin appears to exert a dose-dependent beneficial effect on both the response and survival produced by the intermittent high-dose 5-fluorouracil schedule. This benefit first appears to increase substantially when the leucovorin dose is increased from 120 to 200 mg/m2. Findings identify a testable candidate regimen for selected good risk patients. Full selection criteria remain to be identified.
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PMID:Dose-dependent leucovorin efficacy with an intermittent high-dose 5-fluorouracil schedule. 220 56

A multicenter cooperative study was conducted from June 1988 to July 1989 to evaluate the clinical efficacy of high-dose dl-Leucovorin (dl-LV) and 5-FU treatment in 61 cases of advanced gastric and colorectal cancer. The administration schedule was a 2-hour infusion of dl-LV (500 mg/m2) and an IV bolus of 5-FU (600 mg/m2), given 1 hour after the beginning of LV infusion. Patients (pts.) were treated q week x 6 then evaluated for response. Thirty one gastric cancer pts. were divided into two groups; nine pts. treated with 30 min. infusion of 5-FU, and the remaining 23 pts. treated with IV bolus. PR was obtained in 2/9 (22.2%) and in 7/22 (31.8%) of the first and second group, respectively. An overall response rate was 9/31 (29%). Thirty colorectal cancer pts. were divided the same: 13 pts. treated with 30 min. infusion of 5-FU and the remaining 17 pts. treated with IV bolus. PR was obtained in 2/13 (15.4%) and in 7/17 (41.2) of the first and second groups, respectively. An overall response rate was 9/30 (30%). Median survival time for the gastric cancer group was 9.4 months, and for the colorectal cancer group was 13.6 months. Toxicity was within acceptable limits. Toxic effects included diarrhea, stomatitis, anorexia and myelohypoplasia. Our data suggests that high dose LV and 5-FU seems to be a very promising combination and warrants a further investigation.
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PMID:[High-dose leucovorin and 5-fluorouracil in advanced gastric and colorectal cancer. High-Dose Leucovorin and 5-FU Study Group]. 226 Aug 72

A multicenter cooperative study was conducted from July 1984 to March 1986 to evaluate the clinical efficacy of sequential MTX-5-FU treatment in 96 cases of advanced gastric cancer and 39 cases of colorectal cancer. 5-FU 600 mg/m2 i.v. was given and MTX 30 mg/m2 (A), 100 mg/m2 (B) and 300 mg/m2 (C) i.v. were given, and the administration interval between MTX and 5-FU was 1 to 3 h for the gastric cancer group, and 7 h for the colorectal cancer group. Leucovorin rescue of 10 mg/m2 p.o. was given 24 h after MTX administration. In the gastric cancer group, the response rate for Regimen A was 23.2% (CR 1 and PR 12) out of 56 evaluable cases, and for Regimen B, 40.5% (CR 1 and PR 14) out of 37 evaluable cases. In the colorectal cancer group, the response rate for Regimen A was 28.6% (PR 6) out of 21 evaluable cases and for Regimen B, 20.0% (PR 3) out of 15 cases. Median survival time for the gastric cancer group was 5.5 months with Regimen A and 7.6 months with Regimen B, and for the colorectal cancer group 10.9 months with Regimen A and 7.9 months with Regimen B. Main adverse effects were marrow impairment and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In this study Regimen B showed relatively good results. In order to evaluate the biochemical modulation occurring with sequential MTX-5-FU treatment, a further phase III study in gastric cancer patients should be conducted.
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PMID:[Sequential methotrexate-5-fluorouracil (MTX-5-FU) treatment of patients with advanced gastric and colorectal cancer. Sequential Methotrexate-5-FU Study Group]. 361 60

Recurrence of gastric cancer or colon cancer was observed in some patients who received 5-fluorouracil (5-FU) high-dose continuous Methotrexate (MTX)-Leucovorin (LV) therapy (FML therapy) previously. 5-FU high-dose 48-hours continuous therapy (5-FU therapy) as maintenance therapy for the patients was performed in the hospital and successively at home. The patients included 3 with recurrent gastric cancer and 2 with recurrent colon cancer: there were 4 males and 1 female, the mean age was 51.8 years (33-59 years). All patients had received FML therapy during the hospital stay before the maintenance chemotherapy at home. 5-FU therapy (30 mg/kg/day x 2 days/w), 30.2 courses on an average (11-40 courses), was performed through a catheter (Port-A-Cath), which was introduced into the right subclavian vein and placed under the skin, with a Baxter infusion pump. The concentration of 5-FU was 197 +/- 172-401 +/- 127 ng/ml between the 2nd and 48th hour. Adverse reaction included anorexia in 5 patients, stomatitis in 4, pigmentation in 4, leukopenia in 3, neuropathy in 2 and alopecia in 1. The therapy was effective for 10.4 months on an average (4-18 months) and the mean survival period was 12.0 months (7-18 months).
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PMID:[Usefulness of 5-FU high-dose continuous therapy at home in patients with recurrent gastric and colon cancer]. 780 45

A phase II study to test the toxicity and the efficacy of a weekly combination of Mitoxantrone, 5-Fluorouracil and L-Leucovorin (MFL) was carried out in 43 patients with metastatic breast cancer. Chemotherapy consisted of mitoxantrone 4 mg/m2, 5-fluorouracil 375 mg/m2, and L-leucovorin 100 mg/m2 on day 1, weekly. Patient characteristics were: median age 53 years (range 36-65); estrogen receptor (ER) status was known in 26 patients and of these 15 (57.7%) patients were ER-positive and 11 (42.3%) ER-negative. Of the 43 patients, 25 (58.1%) and 18 (41.9%) patients had received prior adjuvant chemotherapy and prior adjuvant endocrine treatment, respectively. MFL was administered to 22 (51.1%) patients as first line chemotherapy for advanced disease, while 21 (48.9%) patients had received 1 to 2 cytotoxic regimens for metastatic disease. The dominant sites of metastases were: soft tissue in 11 (25.5%) patients, bone in 8 (18.6%) patients and viscera in 24 (55.9%). All patients were assessable for toxicity: only 8 patients experienced WHO grade 3 leukopenia. Thrombocytopenia, diarrhea, stomatitis, and nausea/vomiting were negligible. Anemia and alopecia were not observed. Thirty-nine patients were assessable for response: overall response rate was 28.2% (complete response 7.7% and partial response 20.5%). Median duration of response was 12 months (range 6-34). Patients with no prior anthracyclines had a 42.1% response rate compared to 15% in patients who had received anthracyclines. Median overall survival of the 43 patients was 6 months (range 1-34). Weekly MFL is a well-tolerated and a moderately effective regimen for the treatment of metastatic breast cancer.
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PMID:Phase II study of weekly mitoxantrone, 5-fluorouracil, and leucovorin in metastatic breast cancer. 794 11

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


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