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At least 1,423 records · Page 79Linked to original sources
PubMed2002

Irinotecan (CPT-11) in patients with advanced colon carcinoma relapsing after 5-fluorouracil-leucovorin combination.

The purpose of the present study was to investigate the association between performance status (PS) and mean dose of irinotecan (CPT-11) in patients with recurrent advanced colorectal cancer relapsing after 5-fluorouracil and leucovorin chemotherapy. Patients who had completed their last chemotherapy course with 5-fluorouracil and leucovorin for at least 6 weeks and progressed were included. Based on PS, we administered a starting dose of 250 mg/m(2) in patients with a PS 70-80 (group A), and 350 mg/m(2) for those with a PS > 80 (group B). Of a total of 90 treated patients, all were evaluable, 18 had a partial response (PR) (20%), 39 stable disease (43%), and 15 progressed (37%). No significant difference was noticed between patients with PS > or = 90 or < or = 80 (p = 0.925), or between those who received a mean dose of CPT-11 > or = 300 or < or = 300 (p = 0.602), for response, survival and time to progression. Toxicity was increased in group B as expected, with significant differences for acute cholinergic syndrome (p = 0.02), diarrhea after the first 24 h (p = 0.03) and severe diarrhea (p = 0.03). According to these results, we conclude that response to CPT-11 is independent of its dose, and that a dose of 250 mg/m(2) every 3 weeks might be a cost-effective and less toxic alternative in this setting. However, further adequately powered phase II or III randomized studies might be required in order to confirm this observation.

Adult↗
PubMed2002

mdm2-p53 Interaction: lack of correlation with the response to 5-fluorouracil in advanced colorectal cancer.

OBJECTIVE: We investigated the relevance of mdm2 and p53 primary tumour expression to the clinical outcome of a consecutive series of advanced colorectal cancer patients treated with a 5-fluorouracil-based chemotherapy. METHODS: The expression of p53 and mdm2 was analyzed by an immunohistochemical assay in 80 formalin-fixed paraffin embedded primary tumour samples and related to the clinical response to 5-fluorouracil therapy and to the prognosis of the patients. In a subgroup of 46 tumours, the apoptotic index (AI) as determined by the Tunel technique was also assessed. RESULTS: Nuclear immunostaining of p53 and mdm2 was present in 42 and 30% of the cases, respectively. No correlation was demonstrated between p53 and mdm2 expression (rs = -0.01; p > 0.05). With regard to the clinical outcome, no statistical association was demonstrated among p53 and mdm2 expression, AI, probability of clinical response to treatment, time to progression, or overall survival. The subgroup of patients with a p53-negative/mdm2-positive tumour showed a worse response rate (15%); however, mdm2-positive/AI-negative tumours showed a 0% (0/7) probability of a clinical response as compared with 30% (9/30) of the remaining tumour patient subgroups; this also translated in a significantly worse overall survival probability (p = 0.01 by log rank). CONCLUSIONS: The analysis of mdm2 expression does not add significant clinical information in colorectal cancers with a different p53 status. Conversely, further analysis of AI seems to give data of a promising prognostic-predictive value.

Adenocarcinoma↗
PubMedDate not supplied

Increased intestinal permeability correlates with gastrointestinal toxicity among formulations of the fluorouracil analogue tegafur in rats.

BACKGROUND: S-1 is a new antitumor agent which was developed based on biochemical modulation of fluorouracil. S-1 consists of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. S-1 has been reported to enhance therapeutic effects and to reduce the gastrointestinal toxicity as compared with 5-fluorouracil. In this study performed in rats, S-1 was used to assess the relationship between gastrointestinal mucosal toxicity and changes in intestinal barrier function. METHODS: Fifteen rats were equally divided into three groups: group A (untreated controls), group B (FT and CDHP mixture), and group C (FT and CDHP in combination with Oxo). The animals in groups B and C received equitoxic doses of the drugs in their food for 14 consecutive days. The intestinal permeability was determined on the basis of the urinary recovery of orally administered lactulose and mannitol (L/M). Injury to the small intestines was evaluated by light microscopy. The cell surface expression of CD44 was evaluated immunohistochemically. RESULTS: Recovery of L/M in urine (expressed as a fraction of the dose administered) was 0.15 +/- (SE) 0.08, 0.23 +/- 0.13, and 0.09 +/- 0.04 in groups A, B, and C, respectively. The intestinal permeability in group B was significantly higher than that in group C (p < 0.05). Treatment with FT and CDHP (groups B and C) induced injury to the small intestine and decreased expression of CD44 within the intestinal mucosa, but the extent of damage was reduced by coadministration of Oxo (group C). CONCLUSION: This experimental study suggested that the gastrointestinal toxicity resulting from administration of anticancer drugs is accompanied by an impaired gut barrier function measurable as an increase in intestinal permeability to L/M.

Animals↗
PubMed2002

Neoadjuvant chemotherapy with sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin for locally advanced bladder cancer.

INTRODUCTION: Transitional cell carcinoma of the bladder is moderately sensitive to chemotherapy. Notably, the methotrexate, doxorubicin, vinblastine and cisplatin regimen was found to produce a high overall response rate and a modest survival advantage. However, toxicity was significant and the therapy rarely results in long-term disease-free survival. In several clinical series, sequentially delivered methotrexate and 5-fluorouracil followed by leucovorin rescue in expectation of a biochemical modulation has a higher response rate. METHODS: The combination chemotherapy using sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin (MFAP regimen) for locally advanced bladder cancer was evaluated in a neoadjuvant setting. Thirty-seven patients (32 males and 5 females) were enrolled in this study. RESULTS: Six (16.2%) of the patients had complete responses and 26 (70.3%) had partial responses to the therapy amounting to a response rate of 86.5%. At follow-up, 10 of 13 patients (76.9%) who underwent bladder preservation had not developed muscle-invasive recurrence of the disease and kept their bladder. There is no statistical difference of the survival rate between the cystectomy group and the bladder preservation group (p = 0.86). Toxicity was relatively mild but with some severe myelotoxic effects. CONCLUSIONS: MFAP represents an active regimen in the treatment of locally advanced bladder cancer with a moderate toxicity profile.

Aged↗
PubMed2002

Phase II study of repeated single 24-hour infusion of low-dose 5-fluorouracil for palliation in symptomatic hormone-refractory prostate cancer.

BACKGROUND: To assess the efficacy and toxicity of repeated single 24-hour infusion of low-dose 5-fluorouracil for symptomatic hormone-refractory prostate cancer using relevant endpoints of palliation and biological response. PATIENTS AND METHODS: 25 patients with histologically confirmed prostatic adenocarcinoma and symptomatic progressive disease despite one or several hormonal treatments and chemotherapy were included in the study. Treatment consisted of a single 24-hour infusion of 500 mg/m(2) 5-fluorouracil (5-FU) to be repeated on day 21. This regimen was continued until either progression or serious toxicity occurred. Response was assessed by serial measurements of serum prostate-specific antigen (PSA) as well as by health-related quality-of-life instruments (EORTC QLQ-C30 and McGill-Melzack Present Pain Intensity Scale) every 3 weeks. In 10 patients with bidimensionally measurable metastases, objective responses were assessed every 3 months. RESULTS: A mean number of four courses of repeated single 24-hour infusion of 5-FU was administered (range 2-6). Toxicity was absent or mild, and no patient had to be withdrawn from therapy. All patients required analgesics prior to treatment and only 3 patients experienced a significant reduction in pain for 9 weeks, the remaining patients experienced no deterioration for a mean duration of 12 weeks (6-18 weeks). Five patients (20%) demonstrated a biological response of a 50% or greater decrease in PSA from baseline, including 2 (12%) with a 75% or greater decline for 10 weeks (range 6-16 weeks). One partial remission was observed among 10 patients with measurable lesions lasting 12 weeks; 4 patients had stable disease with a mean duration of 12 weeks. Mean survival time from the onset of treatment with 5-FU was 7 months (2-12 months). CONCLUSIONS: Though less toxic than other 5-FU regimens, repeated single low-dose 24-hour infusion is of no significant benefit in patients with symptomatic hormone-refractory prostate cancer.

Adenocarcinoma↗
PubMed2004

Safety and efficacy of S-1, a novel oral fluorouracil antitumor drug, for a chronic renal failure patient maintained on hemodialysis.

OBJECTIVE: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. METHODS: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0-24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. RESULTS: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0-24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). CONCLUSION: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.

Administration, Oral↗
PubMed2004

Report of an early stopped randomized trial comparing cisplatin vs. cisplatin/ifosfamide/ 5-fluorouracil in recurrent cervical cancer.

This paper reports on an early stopped prospective randomized phase III trial comparing cisplatin, ifosfamide and 5-fluorouracil (PIF) with cisplatin monotherapy in the treatment of recurrent cervical cancer. The aim of the study was to compare response rates, survival, side effects and quality of life. Cisplatin monotherapy was given in a dose of 37.5 mg/m(2) on days 1 + 2 of 4-week schedules. In the PIF regimen, cisplatin was given in the same manner, ifosfamide in a dose of 2 g/m(2) on days 1 + 2 together with mesna 0.5 g/m(2), 5-fluorouracil 500 mg/m(2) on days 1 + 2, and folinic acid 30 mg/m(2) also on days 1 + 2. This regimen was also given in 4-week schedules. The intention had been to include 200 patients in the trial but because of poor accrual the trial was stopped prematurely. Twenty-four patients were included, 3 of which not eligible, and of the remaining 21 patients, 11 were randomized to the cisplatin group and 10 to the PIF group. Median survival for the cisplatin group amounted to 13 months and for the PIF regimen to 12.3 months. The most important side effects were hematologic, with more thrombocytopenia and leukopenia in the PIF regimen. The response rate for the PIF regimen was 40% (4 partial remissions) and 9% for the cisplatin group (1 complete remission). No firm conclusions can be drawn from this trial due to the low number of participants. Still, we believe that the response and survival rates observed with PIF are interesting and that it is important to report all trials, even if they are stopped earlier than intended.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Upregulation of enzymes metabolizing 5-fluorouracil in colorectal cancer.

BACKGROUND: The purpose of this study was to compare the activities of various enzymes, participating in the metabolism of 5-fluorouracil, between colorectal cancer and nontumor tissues and to investigate the association of the enzyme activities with clinicopathological backgrounds. METHODS: Activities of seven enzymes involved in nucleic acid metabolism--orotate phosphoribosyltransferase (OPRT), ribonucleotide reductase (RNR), thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, uridine phosphorylase and thymidine kinase (TK)--were measured in tumor and nontumor tissues from 28 patients who were operated on for colorectal cancers. RESULTS: OPRT, thymidylate synthase, RNR, thymidine phosphorylase, uridine phosphorylase and thymidine kinase activities were significantly higher in tumor areas than in nontumor areas. OPRT showed the highest T/N ratio (the ratio of each enzyme activity in tumor areas to that in nontumor areas). The T/N ratio of RNR activity showed a tendency to be associated with lymph node metastasis and Dukes classification. CONCLUSION: The results suggest that OPRT is a main enzyme participating in the phosphorylation of 5-fluorouracil and has an important role in tumor growth. The T/N ratio of RNR may be predictive of tumor progression.

Adult↗
PubMed1978

[5-fluorouracil inhibits the collagenolytic activity of invasive colonic adenocarcinomas in vitro].

By means of a biological assay for the enzyme collagenase the activity of this protease was examined in 12 invasive adenocarcinomas of the colon. In spite of considerable quantitative differences collagenolytic activity in the dimensions of 10(-3) units/mm theta tissue could be revealed in all cases. EDTA inhibited the reaction by 19%, normal human serum by 23% in the average, whereas 1,10-0-phenanthroline, D-penicillamine as well as the cytostatic 5-fluorouracil resulted in nearly total inhibition. It can be suggested that the activity of the colonic carcinoma is not derived from granulocytes, serum, or normal mucosa, but from the tumor itself. Contrasting to the limited inhibition by normal serum inhibitors, the enzyme is nearly fully inhibited by 5-fluorouracil.

Adenocarcinoma↗
PubMed1979

[5-fluorouracil inhibits bacterial collagenase and the collagenolytic system of a human rhabdomyosarcoma].

Protease inhibitory activity of eight cytostatic drugs on 5 proteases was tested by applying an immunoelectrophoretic system, a rhabdomyosarcoma's collagenolytic activity was investigated and inhibition studies were performed. We found 5-fluorouracil stopping collagenolytic activity of clostridial origin and the enzyme released by the tumor. No other cytostatic drug showed protease inhibition. The collagenolysis of the rhabdomyosarcoma was examined for its origin. Negative inhibition studies with ethylene-diamine-tetraacetate make the leukocyte origin highly improbable so that one can suggest that the hydrolytic enzyme derived from the tumor. Our findings could contribute to characterize the enzyme released by the tumor. We suggest its role as a mediator of invasion and metastasis and on the other hand we detected its relatively specific inhibitor, 5-fluorouracil, which could influence tumorous and normal growth, regeneration and the intermediary protein metabolism.

Cells, Cultured↗
PubMed1980

Combination chemotherapy of advanced colorectal cancer with triazinate and ICRF-159 after failure of 5-Fluorouracil.

13 patients with advanced measurable colorectal cancer, having failed chemotherapy including fluorouracil, were treated on a weekly schedule with ICRF-159, 1.0 g/m2, and triazinate, 250 mg/m2. Only 1 patient had an objective partial remission, lasting 6 months. Toxicity was moderate, but acceptable. Since each of these drugs had been reported to have a 14-17% response rate in similar patient populations, the combination in the present schedule would appear to offer no benefit compared to the single agents, and cannot be recommended for further use in failure of 5-Fluorouracil therapy.

Clinical Trials as Topic↗
PubMed1983

Comparative study on the cytostatic effects and the tissue distribution of 5-fluorouracil in a free form and bound to polybutylcyanoacrylate nanoparticles in sarcoma 180-bearing mice.

The binding of 5-fluorouracil to polybutylcyanoacrylate nanoparticles yielded an enhanced efficacy against Crocker sarcoma S 180 and a higher toxicity of the drug measured by induced leukopenia, body weight loss and premature death. The efficacy was further increased by an increase in the polymer-to-drug ratio. The nanoparticles yielded a prolonged persistence of the 5-fluorouracil in all organs examined including the tumor. These particles hold promise as carriers for cytostatics, since their distribution may be favorably altered by coating them with certain proteins or surfactants or by the attachment of monoclonal antibodies.

Animals↗
PubMed1988

Carcinoma-associated hemolytic-uremic syndrome in a patient receiving 5-fluorouracil-adriamycin-mitomycin C combination chemotherapy.

A patient receiving the antitumor agent mitomycin C (MMC) in combination with 5-fluorouracil and adriamycin because of adenocarcinoma of Vater's papilla manifested hemolytic-uremic syndrome (HUS) after five cycles of 5-fluorouracil-adriamycin-MMC combination chemotherapy. The syndrome most likely was caused by MMC, since an association between HUS and the use of MMC has been observed. We report on the clinical course in such a patient and review the pertinent literature.

Adenocarcinoma↗
PubMed1989

Primary treatment of regional and disseminated pancreatic cancer with hexamethylmelamine, mitomycin C and 5-fluorouracil infusion.

Hexamethylmelamine, mitomycin C and 5-fluorouracil infusion (HexMF) achieved a median survival of 9 months for the 45 patients with either metastatic stage III or unresectable stage II carcinoma of the pancreas. Fifteen percent survived 2 years. Of 32 patients with measurable tumors, 7 had partial and 3 had minor responses (31%); an additional 44% has stable disease for 3 months or more. Response was associated with a 17-month median survival. These findings are indications for further evaluation of both dosage-intensive 5-fluorouracil infusions alone and HexMF as an alternative to streptozotocin- or adriamycin-containing regimens. Patients with nonmeasurable disease are candidates for survival-oriented phase III studies.

Altretamine↗
PubMed1991

Ifosfamide, methotrexate and 5-fluorouracil for pretreated advanced breast cancer.

A total of 51 fully evaluable patients with advanced and intensively pretreated breast cancer were treated with a combination chemotherapy of ifosfamide plus mesna, methotrexate and 5-fluorouracil. All patients had received at least one series of combined chemotherapy, 30 patients had received more than one combination and 41 patients had had anthracyclines before. Metastatic lesions in more than one site were found in 42 patients, and 24 patients had metastatic liver lesions. Partial remission was achieved in 10 patients (20%) and no change in 16 patients (31%). Survival was almost identical in both groups of responding patients and significantly shorter in treatment failures. Response was favorable in patients without pretreatment with anthracyclines. Two patients who received this protocol directly after progression with cyclophosphamide, methotrexate and 5-fluorouracil (CMF protocol) responded with a partial remission. Median time to progression was 7 months for partial responders and 4.5 months for patients achieving a no-change status. Median survival was 8 months for all patients. Toxicity was tolerable. Leukocytopenia and thrombocytopenia were treatment-limiting parameters. Overall, this protocol is well tolerable and effective in breast cancer patients with advanced disease and in intensively pretreated patients.

Adult↗
PubMedDate not supplied

Treatment of metastatic colorectal cancer patients with 5-fluorouracil in combination with recombinant subcutaneous human interleukin-2 and alpha-interferon.

We treated 14 patients with progressive metastatic colorectal cancer, using a combination of subcutaneous recombinant human interleukin-2 (4.8 x 10(6) IU/m2 three times daily on days 1 and 22, and twice daily on days 2 and 23, followed by 2.4 x 10(6) IU/m2 twice daily on days 3-5, 8-12, 24-26, and on 5 consecutive days per week, starting day 29), recombinant human interferon-alpha 2a (5.0 x 10(6) U/m2 thrice weekly), and 5-fluorouracil (750 mg/m2 i.v. bolus on days 15-19, and at weekly intervals thereafter, with a 1-week off-therapy interval every 4 weeks). Therapy was continued until disease progression occurred. Four (29%) and 8 (57%) evaluable patients achieved partial remission and stable disease, respectively; median response duration was 5.9 months. Toxicity of this regimen was moderate; the most common side effects were thrombocytopenia, leukopenia, nausea/vomiting, anorexia, malaise and fevers in all patients, along with diarrhea (63%) and mucositis (54%). Less than 10% of patients developed WHO grade IV toxicity; no toxic deaths occurred. Efficacy of this combination was not substantially different from alternative 5-fluorouracil-based regimens.

Adult↗
PubMedDate not supplied

Severe cardiotoxicity of high-dose 5-fluorouracil in combination with folinic acid, cisplatin and methotrexate in a 14-year-old boy with nasopharyngeal carcinoma (Schmincke tumor).

Cardiotoxicity by 5-fluorouracil has been reported as a rare complication in treatment protocols for adult patients with different malignant diseases. The combination with folinic acid as a biomodulatory substance and other cytotoxic drugs has been introduced to render protocols more effective and less toxic. We report severe but completely reversible cardiotoxicity of a treatment protocol for nasopharyngeal tumor (Schmincke tumor) of pediatric patients consisting of 5-fluorouracil, methotrexate, cisplatin and folinic acid in a 14-year-old boy who had no preexisting cardiac disease. The pathomechanism is briefly discussed.

Adolescent↗
PubMed1979

Treatment of basal cell carcinoma of the skin with 5-fluorouracil ointment. A 10-year follow-up study.

During the period 1966-1968, 88 patients with a total of 95 basal cell carcinomas were treated with 5% 5-fluorouracil ointment. A follow-up study carried out from November 1977 to January 1978 revealed a total of 12 recurrences in 56 surviving patients with 56 basal cell carcinomas. The recurrence rate is thus 21.4%. It is concluded that there is hardly any indication for using 5-fluorouracil in local treatment of nodular basal cell carcinoma.

Administration, Topical↗