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PubMed1990

Phase I study of a 120-hour continuous intravenous infusion of 5-fluorouracil in pediatric patients with recurrent solid tumors: a Pediatric Oncology Group study.

To determine the maximum tolerated dose of 5-fluorouracil administered as a 120-hour continuous intravenous infusion to pediatric patients, we performed a phase I study using a starting dosage of 900 mg/m2/day. The maximum tolerated dosage (MTD) was 1,100 mg/m2/day. At this dosage level 40% of courses were complicated by grade 3 mucositis. Three additional patients were treated at the dosage level of 1,000 mg/m2/day after the MTD was determined. We recommend the dosage level of 1,000 mg/m2/day for phase II studies of 5-fluorouracil administered as a 120-hour continuous intravenous infusion to pediatric patients.

Adolescent↗
PubMed1997

19F NMR monitoring of in vivo tumor metabolism after biochemical modulation of 5-fluorouracil by the uridine phosphorylase inhibitor 5-benzylacyclouridine.

A uridine phosphorylase inhibitor, 5-benzylacyclouridine (BAU), has been utilized as biochemical modulator of 5-fluorouracil (5-FU) anti-tumor activity in a murine tumor model. The effect of BAU on 5-FU metabolism has been evaluated using in vitro and in vivo 19F NMR spectroscopy. The analysis of the NMR data revealed an increased formation and retention of fluorouracil nucleotides and fluorouridine in colon 38 tumors treated with the regimen containing BAU and a reduction in 5-FU catabolites (alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine). In the normal tissues evaluated, the presence of BAU did not significantly alter the metabolism and presence of fluoropyrimidine species, indicating a more selective effect on tumor tissues. Therapy experiments on C57/BL6 mice bearing colon 38 tumor showed that the administration of 120 mg/kg BAU 30 min before 5-FU at 85 mg/kg, on a weekly basis, resulted in an increased antineoplastic effect compared to the same dose of 5-FU alone. A smaller dose of 5-FU (60 mg/kg) also administered 30 min after 120 mg/kg BAU caused a reduction in tumor growth similar to 5-FU alone. The addition of BAU to 5-FU (85 mg/kg) resulted in a slight increase, although statistically nonsignificant, in host toxicity without causing any toxic death during the chemotherapeutic treatment. 19F NMR spectroscopy is here shown to be a powerful technique to evaluate changes in the metabolism of fluoropyrimidines after the use of biochemical modulator and to allow a correlation between improved therapeutic response with the biochemical effects generated in tissues.

Animals↗
PubMed1988

Direct 19F NMR spectroscopic observation of 5-fluorouracil metabolism in the isolated perfused mouse liver model.

A direct analysis of 5-fluorouracil (FUra) metabolism in the isolated perfused mouse liver was carried out using 19F NMR spectroscopy. In livers treated with low (30 mg/kg body weight (b.w.] or high (180 mg/kg b.w.) doses of FUra, with (180 mg/kg b.w.) or without thymidine (dThd), FUra was rapidly catabolized to alpha-fluoro-beta-ureidopropionic acid (FUPA) and alpha-fluoro-beta-alanine (FBAL), the latter usually becoming by far the major catabolite. The first catabolite of FUra, 5,6-dihydro-5-fluorouracil (5FUH2), was never detected both in the liver and in perchloric acid (PCA) extracts. In the latter, it was generally split into three signals, the major one being attributed to 5-fluorouridine-5'-monophosphate. Moreover, when the liver was treated with high doses of FUra and dThd, a signal for fluoronucleoside was observed in the liver, in PCA extracts and in perfusate where it was attributed to 5-fluoro-2'-deoxyuridine (FdUrd). The injection of concurrent dThd with the high dose of FUra led to a marked reduction of catabolism due to competitive inhibition of dihydrouracil dehydrogenase. Moreover, a significant formation of FdUrd was noticed whereas 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) was not detected. dThd therefore inhibits the conversion of FdUrd to FdUMP.

Animals↗
PubMed2002

Correlation between cell survival, clonogenic activity and micronuclei induction in DMBA-OC-1R cells treated with immunospecific albumin microspheres containing cisplatin and 5-fluorouracil.

An ideal chemotherapeutic strategy would be to deliver a high concentration of drug that would be released in sustained small amounts from targeted microspheres to effectively kill only the tumour cells and thus reduce toxicity to normal tissue. Clonogenic and cell survival growth curve assays, as well as the micronucleus assay, were used to determine the feasibility of employing targeted immunomicrospheres in the treatment of cancer. Cells of a rodent ovarian carcinoma cell line, were exposed to cisplatin and 5-fluorouracil, either as free drug or encapsulated in albumin microspheres that were either conjugated to monoclonal antibodies or not. In cell survival growth curve assays, cell survival was reduced to 1.2% of the control when cells were treated with drug-containing immunomicrospheres. 3.2-fold more micronuclei were found in those cells that had been exposed to the drugs in immunomicrospheres than in those subjected to untargeted microspheres. All three assays demonstrated that the targeted immunomicrospheres were more effective in delivering cisplatin and 5-fluorouracil directly to the cells than the unconjugated microspheres, thus suggesting that targeted chemotherapy might be a more effective option in the treatment of cancer.

Adenocarcinoma↗
PubMed1997

Mitigating effects of interleukin 11 on consecutive courses of 5-fluorouracil-induced ulcerative mucositis in hamsters.

Ulcerative mucositis is a painful, debilitating and dose-limiting toxicity of cancer chemotherapy. Current treatment is largely palliative and no adequate preventive treatment exists. Recently, we reported that recombinant human(rh) interleukin 11 (IL-11) favourably modified the course of mucositis following a single stomatotoxic regimen of 5-fluorouracil in hamsters. Although potentially beneficial, the clinically relevant issue of mucositis and myelosuppression during multicourse chemotherapy treatment was not addressed. The present study was undertaken to evaluate the effect of rhIL-11 on two consecutive courses of mucositis and myelosuppression in hamsters. Ulcerative mucositis was induced using a standardized protocol consisting of 5-fluorouracil (60 mg/kg) on days 1 and 2 followed by superficial irritation of the buccal mucosa on day 4. Animals treated with 100 microg of rhIL-11 for 12 consecutive days following each regimen of chemotherapy experienced a reduction in the incidence, severity, and duration of mucositis, a reduction in weight loss, and less morbidity and mortality relative to control animals. Bone marrow cellularity and function was not adversely affected by rhIL-11 treatment. The present study is consistent with the potential use of rhIL-11 treating patients at risk of developing ulcerative mucositis while undergoing intensive multicourse chemotherapy treatment.

Animals↗
PubMed1994

Phase II evaluation of 5-fluorouracil and low-dose leucovorin in cisplatin-refractory advanced ovarian carcinoma.

Thirty-nine women with advanced, recurrent epithelial ovarian carcinoma who failed prior treatment with a platinum-based regimen were treated with leucovorin, 20 mg/m2 intravenously followed by 5-fluorouracil, 425 mg/m2 intravenously, daily for 5 consecutive days every 5 weeks in a phase II trial. Partial regressions were seen in 3 of 15 (20%) measurable disease patients, and objective regressions were seen in 3 of 14 (21%) evaluable/nonmeasurable disease patients. A 50% or greater decrease in CA-125 level was observed in 3 of 10 (30%) patients with no objectively evaluable or measurable disease. Overall objective response rate was 23% (95% confidence interval: 11 to 39%) in all 39 patients evaluated, with a median time to progression of 3 months and overall median survival of 7 months. Toxicities were acceptable and consisted of neutropenia, thrombocytopenia, stomatitis, and mild diarrhea. 5-Fluorouracil, as administered in this protocol, had modest antitumor activity in cisplatin-refractory ovarian carcinoma of short duration and minimal toxicity.

Adenocarcinoma↗
PubMed1996

Treatment of advanced or recurrent endometrial carcinoma with combination of etoposide, cisplatin, and 5-fluorouracil: a phase II study.

Forty-nine consecutive patients with metastatic or recurrent endometrial carcinoma were treated with a monthly combination chemotherapy consisting of VP 16-213 80 mg/m2 i.v. Days 1-3, 5-fluorouracil (5-FU) 600 mg/m2 i.v. Days 1-3, and cisplatin 35 mg/m2 i.v. Days 1-3. The objective response rate was 41% (95% CI, 27-54%) with 14.3% complete responses. The median survival duration was 14 months. The median response duration was 12 months. The estimated median survival for responders was 20 months. Three patients are still free of disease 5 years after treatment. The major toxic effects were myelosuppression (less than 25% of grade III and IV leucopenia, and 14% grade III and IV thrombocytopenia). Grade III peripheral neuropathy was observed in five patients. Cisplatin administration had to be stopped due to renal toxicity in six patients. No treatment-related deaths occurred. The combination of etoposide, 5 fluorouracil, and cisplatin is an effective regimen with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma.

Adenocarcinoma↗
PubMed1997

Phase II trial of doxorubicin, 5-fluorouracil, etoposide, and cisplatin in advanced or recurrent endometrial carcinoma.

We have previously reported an overall response rate of 41% and a median survival duration of 14 months in a series of 49 patients with metastatic or recurrent endometrial carcinoma treated by a combination of etoposide, 5-fluorouracil, and cisplatin. In order to increase response rate and survival duration, doxorubicin was added to this combination. From August 1992 to January 1996, 20 consecutive patients were treated with a monthly combination chemotherapy consisting of doxorubicin 30 mg/m2 i.v. Day 1, 5-fluorouracil 600 mg/m2 i.v. Days 1 to 3, etoposide 80 mg/m2 i.v. Days 1 to 3, and cisplatin 35 mg/m2 i.v. Days 1 to 3 (AFEP). All patients were evaluable for response and toxicity. Median age was 62 years (range 45-72). Two to eight cycles were delivered (median 5). Two of 20 patients had complete response and 7 of 20 had partial response. The objective response rate was 45% (CI 95%: 23-68%). The median survival duration was 17 months. The median progression-free survival was 8 months. Major toxic effect was myelosuppression: 75% of grade 3 and 4 leukopenia and 20% of grade 3 and 4 thrombocytopenia. Seven patients (35%) developed infection and 4 (20%) were hospitalized once or more for toxicity. These results indicate that AFEP is an effective combination therapy in metastatic endometrial carcinoma but its toxicity is unacceptable.

Adenocarcinoma↗
PubMed1999

Pilot study of concurrent cisplatin, 5-fluorouracil, and external beam radiotherapy prior to radical surgery +/- intraoperative electron beam radiotherapy in locally advanced cervical cancer.

PURPOSE: The purpose of this study was to describe the feasibility of a combined preoperative chemoradiation program followed by radical surgery in advanced cervical cancer. MATERIALS AND METHODS: From February 1988 to April 1997, 40 patients with carcinoma of the cervix were treated with preoperative external beam radiotherapy to 45 Gy in 5 weeks. Patients received concurrent continuous infusion cisplatin (20 mg/m2) and 5-fluorouracil (1500 mg) chemotherapy during the first (days 1-4) and fifth (days 22-25) weeks of the radiation course. Radical surgery was performed 4-6 weeks after the completion of the preoperative treatment. Intraoperative radiotherapy was given to 20 patients, based on intraoperative assessment. RESULTS: Toxicity associated with chemoradiation was usually mild except in two patients who presented WHO grade 4 bone marrow aplasia. Three patients developed postoperative ureterovaginal fistula, and five patients developed long-term hydronephrosis that needed ureteral stenting. Clinical response was observed in 95% of the patients (55% complete response). The analysis of the surgical specimens revealed complete pathological response in 67.5% of the cases and partial pathological response in 32.5%. As expected, the degree of pathological response was predicted by the degree of clinical response (P = 0.001). Nine-year local control, distant metastases-free survival, disease-free survival, and overall survival were 86, 84, 81, and 85%, respectively. Patients displaying a complete pathological response had statistically significant improved local control (P = 0.004), distant metastases-free survival (P = 0.009), disease-free survival (P = 0.002), and overall survival (P = 0.038). CONCLUSIONS: Cisplatin plus 5-fluorouracil preoperative chemoradiation is active and usually well tolerated in locally advanced carcinoma of cervix, inducing a high rate of clinical and pathological complete responses. When this therapy is followed by radical surgery, the local control rates are excellent, even in patients with advanced stages or poor response. These improved local control rates may be achievable only through extensive surgical resection, with a parallel increase in the complication rates.

Actuarial Analysis↗
PubMed2000

Sequence-dependent toxicity profile in modified FAMTX (fluorouracil-adriamycin-methotrexate) chemotherapy with lenograstim support for advanced gastric cancer: a feasibility study.

For advanced irresectible gastric cancer, sequential high-dose methotrexate and 5-fluorouracil (both on day 1) combined with adriamycin on day 15 (FAMTX regimen), cycled every 28 days, is a fairly effective but toxic treatment, with a high incidence of neutropenic fever, dose reductions and dose delays. In order to improve FAMTX toxicity, we studied the feasibility of two modified FAMTX regimens with lenograstim support. Seven advanced gastric cancer patients were treated with all three FAMTX drugs on day 1 followed by lenograstim 150 microgm(-2)for 10 days, in 21-day cycles (FUMA regimen). The next seven patients were treated with the same drugs at the same doses, but with adriamycin 1 day prior to methotrexate and 5-fluorouracil administration (AFUM regimen). Patients were monitored for toxicity, response, and survival. The total number of courses was 27 for FUMA and 35 for AFUM with a median of four courses per patient in each cohort. In the FUMA regimen, considerable toxicity consisting of mucositis and fatigue as well as grade 4 neutropenia occurred, and forced four out of seven patients to stop treatment. The consecutive AFUM regimen showed only mild toxicity, and all patients could finish treatment without dose reductions or delays. We found unanticipated and probably sequence-dependent toxicity profiles in two investigational, modified FAMTX schedules with lenograstim support, leading to high rates of dose-limiting toxicity in the FUMA regimen as opposed to mild toxicity in the AFUM regimen, even though the same total drug doses and treatment cycle length (dose intensity) were employed.

Adenocarcinoma↗
PubMed1996

Phase II study of 5-fluorouracil and leucovorin in recurrent primary brain tumor.

Thirty patients with recurrent primary brain tumors were treated with a combination of 5-fluorouracil and leucovorin. There were three responses seen. Toxicity consisted of stomatitis, diarrhea, and hematological suppression. 5-fluorouracil and leucovorin would appear to be minimally effective in recurrent brain tumors.

Adult↗
PubMed1990

An evaluation of combination 5-fluorouracil and spirogermanium in the treatment of advanced colorectal carcinoma.

Seventeen patients with advanced colorectal carcinoma were treated with a combination of 5-fluorouracil and spirogermanium, a recently developed azaspiran-germanium compound remarkable for its lack of hematologic, gastrointestinal, renal or hepatic toxicity. Response to treatment and the incidence and severity of toxicity were evaluated. No patient achieved a complete response; there were three partial responses. Toxicity was unexpectedly frequent and severe; one patient was removed from study early due to intractable diarrhea, and there were two toxic deaths, both attributable to neutropenia and sepsis. Significant toxicity occurred in all seventeen patients, including three instances of Grade 3 or 4 hematologic toxicity. Given the low response rate and high incidence of life-threatening toxicity, we do not recommend further evaluation of this schedule of 5-fluorouracil and spirogermanium in the treatment of colorectal carcinoma.

Adult↗
PubMed1980

Inhibition of murine colon adenocarcinomas and Lewis lung carcinoma by 1-hexylcarbamoyl-5-fluorouracil.

1-Hexylcarbamoyl-5-fluorouracil (HCFU) and its parent compound 5-fluorouracil (5-FU) were tested PO for antitumor activity against mouse colon adenocarcinoma 26 (colon 26), colon adenocarcinoma 38 (colon 38), and Lewis lung carcinoma. The drugs were given orally at 2--4 days intervals for a total of ten doses. 5-FU was moderately active against colons 26 and 38 but not against Lewis lung carcinoma. In this treatment regimen the most impressive antitumor activity was obtained with HCFU against colons 26 and 38, especially colon 38 tumor. At 300 mg HCFU/kg, one out of seven mice inoculated with colon 26 and five out of ten mice inoculated with colon 38 became tumor-free. HCFU, however, was marginally effective in the prolongation of survival time of mice bearing Lewis lung carcinoma. 5-FU is approximately twice as active as HCFU against cultured cell lines from colon 26, colon 38, and Lewis lung carcinoma. Lewis lung carcinoma cells were most sensitive against HCFU, which is in contrast to the results obtained in the in vivo experiment. The IC50 value of HCFU against Lewis lung carcinoma cells was approximately half that against colon 26 and colon 38 cells. This higher sensitivity of Lewis lung cells against HCFU could be explained by the higher cellular uptake of the drug.

Adenocarcinoma↗
PubMed1983

Combination of dacarbazine, mitomycin C, 5-fluorouracil and vincristine in advanced colorectal cancer.

Thirty patients with advanced measurable colorectal cancer received monthly courses of a combination of dacarbazine, mitomycin C, 5-fluorouracil, and vincristine (FIVMit-Or). Four of the patients had received prior chemotherapy. Two patients were not evaluable for response. Objective response was obtained in four patients. Severe toxicity was encountered in 11 patients. It is concluded that unlike the four-drug combination of 5-fluorouracil, DTIC, vincristine and BCNU (FIVB), the present regimen did not have significant antitumour activity in advanced colorectal cancer.

Adult↗
PubMed1986

Potentiation of antitumor activity of 1-phthalidyl 5-fluorouracil by acetazolamide.

The effect of acetazolamide (A.A.) on the antineoplastic activity of 1-phthalidyl 5-fluorouracil (PH-FU) against rat and mouse solid tumors was examined. A.A., an inhibitor of liver PH-FU hydrolase, had no antitumor activity but greatly enhanced the activity of PH-FU when coadministered. The potentiation was evaluated in terms of suppression of tumor growth and prolongation of the life-span of tumor-bearing animals. Studies also revealed that A.A. elevated the concentration of PH-FU in tumor tissues, where 5-fluorouracil is slowly liberated from PH-FU. The results are consistent with the hypothesis that A.A. prevents enzymic degradation of PH-FU in the liver and promotes its distribution into target organs.

Acetazolamide↗
PubMed1978

Antitumor activity of 1-alkylcarbamoyl derivatives of 5-fluorouracil in a variety of mouse tumors.

The antitumor properties of 1-alkylcarbamoyl derivatives of 5-fluorouracil were examined in various mouse tumor systems to select promising compounds for clinical use. Almost all alkylcarbamoyl derivatives were active against various tumors when given by oral administration. Among them, 1-methyl, 1-ethyl, 1-isopropyl, 1-hexyl and 1-octyl carbamoyl derivatives of 5-fluorouracil were moderately or markedly active in six mouse tumor systems tested. However, 1-methyl, 1-ethyl, and 1-isopropyl carbamoyl derivatives were toxic to mice, though not lethal. As a result, 1-hexyl and 1-octyl carbamoyl derivatives were selected as the best candidates for antitumor agents in further study.

Adenocarcinoma↗
PubMed1985

Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) in advanced gastric cancer.

Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m2 IV on days 1-5, adriamycin 50 mg/m2 IV on day 1, cisplatin 20 mg/m2 IV on days 1-5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patient showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2 X 10(9)/l (range 0.7-4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).

Adenocarcinoma↗
PubMed1982

Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients.

Plasma concentrations of 5-fluorouracil (FU) and its primary catabolite, 5', 6'-dihydro-5-fluorouracil (DHFU) were measured using gas-liquid chromatography after single-dose therapy with 7.2-14.4 mg/kg. Because of the limited sensitivity of the assay for drug levels in plasma, the urinary excretion of FU and metabolites was investigated using an ion-specific electrode after either a single bolus (7.0-9.6 mg/kg) or multiple-dose therapy (6.4-7.4 mg/kg/day). Half-life values for the elimination of FU from plasma (mean, 123.5 min) were greater in each patient than for the catabolite (mean, 109.2 min). Values of the area under the curve for FU profiles varied between patients (mean +/- SE, 12.7 +/- 1.9 micrograms X h/ml) by comparison with the relatively constant values for curves of DHFU concentrations (mean +/- SE, 2.8 +/- 0.15 micrograms X h/ml). In pharmacokinetic profiles of urinary excretion a transient phase of convex shape was apparent after 80%-98% of single doses of FU was excreted. Half-lives for the elimination of FU in urine were 2.6-5.9 h, which increased to 18-44 h on multiple dosing. The results demonstrate saturation in the elimination of FU after therapeutic doses, and are consistent with the proposal that reduction of FU to DHFU provides the rate-limiting step.

Biotransformation↗