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PubMed1980

Pharmacokinetics of oral and intravenous fluorouracil in humans.

The pharmacokinetics of fluorouracil were examined after single 250-mg iv doses and 500-mg oral doses to female patients with breast cancer. In five patients who received intravenous fluorouracil, the mean peak plasma level of unchanged drug was 13.4 microgram/ml, the elimination half-life was 6.3 min, and the plasma clearance was 1410 ml/min. The last value is similar to the hepatic blood flow. In six patients who received oral fluorouracil, the mean peak value of unchanged drug in plasma, which occurred within 20 min of dosing, was 8.3 microgram/ml, and the fluorouracil elimination half-life was 7.2 min. The overall bioavailability of oral fluorouracil as unchanged drug was 28%, and the variation in plasma drug levels between individuals was similar following oral and intravenous doses. The data provide additional evidence of saturable hepatic metabolism of fluorouracil during the first pass.

Administration, Oral↗
PubMed1984

Re-evaluation of 5-fluorouracil as a single agent for gestational malignant trophoblastic neoplasms.

Large doses of 5-fluorouracil, administered by slow intravenous drip, have proven to be very effective in the treatment of malignant trophoblastic tumors. From 1964 through 1975, 5-fluorouracil was used as a single chemotherapeutic agent in 173 cases of invasive mole and 139 cases of choriocarcinoma. This series of patients was further divided into Group A (212 cases) in which 5-fluorouracil was used as initial therapy, and Group B (100 cases) in which 5-fluorouracil was given to those who developed resistance to 6-mercaptopurine and/or to methotrexate. The overall remission rate in Group A patients was 98.4% for invasive mole and 93.0% for choriocarcinoma. In Group B patients the corresponding remission rate was 93.6% and 71.7%, respectively, indicating that 5-fluorouracil is effective in patients who develop resistance to other antimetabolic agents. The rate of recurrence among 213 patients achieving complete remission during follow-up was 1.4% (3 cases). All of the remaining 210 patients had survived for more than 5 years up to the end of 1981, and 96 patients (45.7%) had survived for more than 10 years. In comparison with other antimetabolites, 5-fluorouracil has the advantages of being more effective and less toxic, and can be administered through multiple routes. Therefore, it has remained the agent of first choice in the chemotherapy of malignant trophoblastic neoplasms.

Enterocolitis, Pseudomembranous↗
PubMed1981

Allopurinol modulation of fluorouracil toxicity.

Considerable interest has developed in the modulation of fluorouracil activity by nucleosides. The toxicity of fluorouracil in mice is known to be reduced by concurrent administration of allopurinol, presumably because biochemical pathways activating fluorouracil in normal tissues are blocked. We have given allopurinol (300 mg t.d.s. PO) concurrently with continuous infusions of fluorouracil (2.0--2.25 g/m2/day X 5) to 34 patients with colorectal cancer and 11 patients with various adenocarcinomas. There were 41 patients assessable for toxicity. Stomatitis was the predominant dose-limiting toxicity (22% grade 1, 19% grade 2, and 27% grade 3 toxicity). Neutropenia (Less Than 1,000/mu l) occurred in 17% patients. Among 26 colorectal cancer patients assessable for response there was a 15.4% response rate. We conclude that allopurinol modulates fluorouracil toxicity in man, allowing a two-fold increase in dose. However, at least in colorectal cancer no greater frequency of tumour response is seen than with lower doses of fluorouracil given by standard schedules of administration without allopurinol.

Allopurinol↗
PubMed2000

Selective augmentations of intratumoral 5-fluorouracil concentration by local immunotherapy with OK-432 and fibrinogen.

PURPOSE: Pyrimidine nucleoside phosphorylase is an enzyme that converts 5'-deoxy-5-fluorouridine into its active metabolite, 5-fluorouracil. In colorectal cancer tissue pyrimidine nucleoside phosphorylase has been proven to be produced by macrophages in the cancer stroma despite presence of the cancer cells. We reported that local immunotherapy with OK-432 and fibrinogen induced aggregation of macrophages in the cancer stroma and enforced their pyrimidine nucleoside phosphorylase expression. Thus it was hypothesized that if colon cancer were treated with 5'-deoxy-5-fluorouridine, the 5-fluorouracil concentration in cancer tissues would be enhanced by local immunotherapy. The present study was conducted to investigate whether local immunotherapy for colon cancer could increase the intratumoral 5-fluorouracil concentration in patients given chemotherapy with 5'-deoxy-5-fluorouridine. METHODS: Twenty patients with resectable colorectal cancer were examined in this study. They were given 5'-deoxy-5-fluorouridine (600 mg/day) orally for seven days preoperatively. Nine randomly selected patients underwent intratumoral injection of OK-432 mixed with fibrinogen, which was performed on the third preoperative day (OK-432 and fibrinogen plus 5'-deoxy-5-fluorouridine group); eleven patients were given oral 5'-deoxy-5-fluorouridine only (5'deoxy-5-fluorouridine group). The 5-fluorouracil concentration in tumor tissue and normal colon mucosa tissue was measured, and the influence of the local immunotherapy was assessed. RESULTS: The 5-fluorouracil concentration in the cancer tissue was increased by the local immunotherapy, whereas that in the normal colon mucosa was not influenced. Thus, the influence of local immunotherapy was selective to the cancer tissue where the mixture of OK-432 and fibrinogen was injected. CONCLUSION: In patients with colorectal cancer, selective high 5-fluorouracil concentration in the cancer tissue could be achieved by a combination of 5'-deoxy-5-fluorouridine and local immunotherapy with a mixture of OK-432 and fibrinogen.

Aged↗
PubMed1995

Phase II study of cisplatin, 5-fluorouracil and interferon-alpha in recurrent carcinoma of the cervix.

Standard cytotoxic regimens have failed to prolong survival in patients with recurrent cervical cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Cisplatin and 5-fluorouracil are one of the most active regimens currently available for recurrent cervical cancer. Interferon-alpha and potentiate the in vitro and in vivo activity of both agents. Therefore, we sought to define the feasibility and activity of adding interferon-alpha to the cisplatin-5-fluorouracil regimen. Patients with histologically proven recurrent cervical carcinoma received interferon-alpha (5 x 10(6) units/m2/day for 5 days) combined with cisplatin (75 mg/m2 on day 1) plus 5-fluorouracil (500 mg/m2/day for 5 days) in recurrent cervical cancer. Twenty-six patients were included in this study and received a total of 95 courses of therapy. All 26 had prior radiotherapy and five had prior chemotherapy. This regimen was relatively well tolerated as toxicity was comparable to that of cisplatin plus 5-fluorouracil alone. Major response occurred in 8 patients (31%) and 5 (19%) had complete responses. The median response duration was 6 months (range, 2-34 months) and the median survival duration was 9 months (range, 2-38 months). The addition of interferon-alpha to cisplatin plus 5-fluorouracil is feasible. Further studies will be necessary to determine if the addition of interferon-alpha to this regimen is superior to cisplatin plus 5-fluorouracil alone.

Adult↗
PubMed2007

The effect of octreotide on healing of injured colonic anastomosis with immediate postoperative intraperitoneal administration of 5-Fluorouracil.

PURPOSE: This study was designed to investigate the effect of octreotide on side effects of immediate usage of 5-fluorouracil after colonic anastomosis. METHODS: Forty male Wistar rats were randomly assigned into four groups and underwent standardized left colonic anastomosis. The rats served as control or received intraperitoneal 5-fluorouracil (20 mg/kg daily), subcutaneous octreotide (20 mug/kg daily), or both. Diarrhea and wound complications were noted during the experiment. The colonic anastomoses were assessed for healing on postoperative Day 7 by determining the anastomotic bursting pressure, performing histologic examination, and measuring the tissue hydroxyproline content, serum malondialdehyde, and nitric oxide levels. Intraperitoneal adhesions and anastomotic leakage were also noted. RESULTS: No statistical significant difference was found between the control and octreotide groups for each of the parameters measured. Immediate 5-fluorouracil use resulted with higher adhesion score (P = 0.002), significant depression in anastomotic bursting pressure (P = 0.0001), histopathologic score (P = 0.0001), hydroxyproline content (P = 0.0001), and increasing nitric oxide (P = 0.0001) and malondialdehyde levels (P = 0.0001) compared with the control group. Diarrhea was seen in 80 percent of the 5-fluorouracil group but in neither the control nor octreotide groups (P = 0.0001 for each comparison). However, all these parameters were ameliorated by use of concomitant octreotide and 5-fluorouracil (P = 0.019, P = 0.023, P = 0.0001, P = 0.006, P = 0.0001, and P = 0.013, respectively). In addition, diarrhea was found to be prevented (P = 0.0001). CONCLUSIONS: The results of this study showed that concomitant octreotide use might prevent the side effects of 5-fluorouracil, such as diarrhea, postoperative adhesion, and delaying the anastomotic healing parameters. In addition, it might reduce tissue damage and inflammation.

Analysis of Variance↗
PubMed2006

Development of 5-fluorouracil loaded poly(acrylamide-co-methylmethacrylate) novel core-shell microspheres: in vitro release studies.

Novel poly(acrylamide-methylmethacrylate) copolymeric core-shell microspheres crosslinked with N,N'-methylene bisacrylamide have been prepared by free radical emulsion polymerization using varying amounts of acrylamide (AAm), methylmethacrylate (MMA) and N,N'-methylene bisacrylamide (NNMBA). 5-Fluorouracil was loaded into these microspheres during in situ polymerization (method-I) as well as by the absorption and adsorption technique (method-II). The core-shell microspheres have been characterized by differential scanning calorimetry (DSC) and X-ray diffractometry (X-RD) to understand about the drug dispersion in microspheres. Scanning electron microscopy (SEM) was used to assess the surface morphology of particles prepared. In vitro release of 5-fluorouracil has been studied in terms of core-shell composition, amount of crosslinking agent and amount of 5-fluorouracil in the microspheres. Core-shell microspheres with different copolymer compositions have been prepared in yields ranging 80-85%. DSC and X-RD techniques indicated a uniform distribution of 5-fluorouracil particles in core-shell microspheres, whereas SEM suggested the formation of well-defined core-shell structures. The in vitro drug release indicated that particle size and release kinetics depend upon copolymer composition, amount of crosslinking agent used and amount of 5-fluorouracil present in the microspheres. Prolonged and controlled release of 5-fluorouracil was achieved when drug was loaded by method-I instead of method-II.

Absorption↗
PubMed1994

Comparative toxicity of mitomycin C and 5-fluorouracil in vitro.

The adjunctive use of antimetabolites has revolutionized surgical procedures to correct glaucoma in the past decade. Although much is known about the in vitro and in vivo actions of 5-fluorouracil and mitomycin C, their use in the eye has raised new questions about cellular toxicity. For example, filtering blebs after a surgical procedure supplemented with mitomycin C are relatively avascular in comparison with those seen with 5-fluorouracil supplementation. We investigated the effect of 5-fluorouracil and mitomycin C on cultured capillary endothelial cells and fibroblasts. The viability and morphologic characteristics of 3T3 fibroblasts and capillary endothelial cells were studied in light of increasing doses of 5-fluorouracil and mitomycin. Both cell types showed similar sensitivity to mitomycin C. However, fibroblasts were far more sensitive to 5-fluorouracil than were the cultured microvascular endothelial cells. Thus 5-fluorouracil appears to be toxic to fibroblasts while sparing vascular endothelial cells, whereas mitomycin C is cytotoxic for both cell types.

3T3 Cells↗
PubMed1994

5-Fluorouracil after primary combined filtration surgery.

We examined the safety and efficacy of 5-fluorouracil in eyes with open-angle glaucoma undergoing combined cataract removal and filtration surgery. We randomly assigned one eye each of 24 patients to receive 5-fluorouracil (five injections of 5 mg during two weeks after surgery) and one eye each of 20 patients to comprise the control group. Preoperatively, the two groups had similar mean intraocular pressure (P = .8) and number of medications (P = .2). The mean intraocular pressure of the 5-fluorouracil group was 18.6 +/- 1.1 mm Hg, with 2.5 +/- 0.3 medications; that of the control group was 18.2 +/- 1.2 mm Hg, with 2.2 +/- 0.2 medications. One year postoperatively, intraocular pressure and the number of medications were significantly reduced by a similar amount in both groups of patients (5-fluorouracil, 14.2 +/- 0.7 mm Hg, 0.8 +/- 0.2 medications; controls, 14.3 +/- 0.6 mm Hg, 1.0 +/- 0.2 medications). Transient superficial punctate keratopathy occurred more frequently (P = .04) in the 5-fluorouracil group (16 of 24 eyes, 67%) than in the control group (seven of 20 eyes, 35%). In our randomized and prospective study, the adjunctive use of 5-fluorouracil did not result in improved control of intraocular pressure one year after combined surgery in eyes with open-angle glaucoma.

Aged↗
PubMed1993

Three-year follow-up of the Fluorouracil Filtering Surgery Study.

Patients who participated in the Fluorouracil Filtering Surgery Study, a clinical trial in which patients were randomly assigned to treatment to determine the efficacy and safety of subconjunctivally injected 5-fluorouracil after filtering surgery in eyes with poor prognoses, were followed up for three years. Treatments in 49 of the 100 eyes in the 5-fluorouracil group and 73 of the 99 eyes (74%) in the standard treatment group were classified as failures, defined by reoperation for control of intraocular pressure or intraocular pressure greater than 21 mm Hg during the first three years postoperatively (P < .001, chi-square). Late-onset leakage of aqueous through the filtering bleb occurred more frequently in the 5-fluorouracil group (seven of 105 eyes, 7%) than in the standard treatment group (none of 108 eyes, 0%) (P = .006, Fisher's exact test). We recommend the use of 5-fluorouracil after trabeculectomy in eyes after previous cataract extraction or unsuccessful filtering surgery. The increased risk of late-onset conjunctival filtering bleb leaks associated with 5-fluorouracil cautions against its routine use in patients with good prognoses.

Fluorouracil↗
PubMed1990

Measurement of 5-fluorouracil and its active metabolites in tissue.

The 5-fluorouracil content of serum, bile, pancreatic juice, liver, pancreas and muscle was measured by reversed-phase high-performance liquid chromatography using a mobile phase of 5 mM 1-heptanesulfonic acid in 5 mM acetic acid. Free or unmetabolized 5-fluorouracil was extracted from samples with a mixture of light petroleum-n-propanol (40:60). The active metabolites of 5-fluorouracil were hydrolyzed with hot perchloric acid to free 5-fluorouracil and the combined 5-fluorouracil content was extracted. The active metabolite fraction was calculated from the difference between the combined and the free fractions. A straight line plot of the peak areas against concentration was achieved and the detection limit was 50 ng/ml. Five minutes after stopping an intravenous infusion of 15 mg/kg of 5-fluorouracil in a dog, the serum contained only the free form, but other body fluids and tissues contained both free and metabolite fractions. The method may be useful to determine the amount of total drug in patient samples.

Animals↗
PubMed2002

Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study.

BACKGROUND: Edrecolomab is a murine monoclonal antibody to the cell-surface glycoprotein 17-1A, which is expressed on epithelial tissues and on various carcinomas. Preliminary data suggested that it might be of use in the adjuvant treatment of patients with resected stage III colon cancer. We did a randomised trial in 27 countries to determine the effect of adding edrecolomab to the combination of fluorouracil and folinic acid in these patients. METHODS: After surgery, 2761 patients were randomly assigned edrecolomab plus fluorouracil-folinic acid (combination therapy [n=912]); fluorouracil-folinic acid alone (chemotherapy [n=927]); or edrecolomab alone (edrecolomab monotherapy [n=922]). Patients were assessed for survival and disease recurrence after surgery. The primary endpoint tested the hypothesis that combination therapy improved overall survival relative to chemotherapy. The key secondary endpoint was to test whether edrecolomab monotherapy was non-inferior to chemotherapy in terms of disease-free survival. Analysis was by intention to treat. FINDINGS: Median follow-up time was 26 months (IQR 20-36). 3-year overall survival on combination therapy was no different from that on chemotherapy (74.7% vs 76.1%, hazard ratio 0.94 [95% CI 0.76-1.15], p=0.53). Disease-free survival was significantly lower on edrecolomab monotherapy than on chemotherapy (53.0% vs 65.5%, 0.62 [0.53-0.73], p<0.0001). Hypersensitivity reactions occurred in 452 (25%) patients receiving edrecolomab, causing treatment discontinuation in 71 (4%). The addition of edrecolomab to chemotherapy did not increase neutropenia, diarrhoea, or mucositis. INTERPRETATION: The addition of edrecolomab to fluorouracil and folinic acid in the adjuvant treatment of resected stage III colon cancer does not improve overall or disease-free survival, and edrecolomab monotherapy is associated with significantly shorter overall and disease-free survival than fluorouracil and folinic acid and is therefore an inferior treatment option. Edrecolomab is well tolerated and its addition to fluorouracil and folinic acid does not increase the toxicity of chemotherapy.

Aged↗
PubMed1994

Risk factors for the development of encapsulated filtering blebs. The role of surgical glove powder and 5-fluorouracil.

PURPOSE: To study risk factors for the development of encapsulated filtering bleb, especially the effect of surgical glove powder and 5-fluorouracil on the development of encapsulated blebs. METHODS: One hundred forty-eight patients who underwent trabeculectomy were prospectively studied. After patient of each surgeon were divided into two subgroups of 5-fluorouracil versus no 5-fluorouracil, each subgroup was then randomized for powder versus powder-free surgical gloves. All patients were followed for at least 2 months (mean, 3.5 months; range, 2-10 months). RESULTS: The overall incidence of encapsulated bleb was 11.2% when an encapsulated bleb was defined by clinical characteristics with a peak intraocular pressure of 26 mmHg or higher. The group that received 5-fluorouracil had a lower incidence of encapsulated blebs despite a higher rate of previous surgeries, whereas the group with powdered gloves had increased incidence. The subgroup in which powder-free gloves were used in conjunction with postoperative injections of 5-fluorouracil had the lowest incidence of encapsulated blebs (2.6%) compared with the other subgroups (12.0%-17.9%) (P = 0.01). CONCLUSION: Combined use of powder-free surgical gloves and 5-fluorouracil may reduce the incidence of encapsulated bleb.

Adult↗
PubMed1997

Pilot study of continuous-infusion 5-fluorouracil, oral leucovorin, and upper-abdominal radiation therapy in patients with locally advanced residual or recurrent upper gastrointestinal or extrapelvic colon cancer.

PURPOSE: The purpose of this study was to develop a satisfactorily tolerated regimen of radiation therapy, continuous infusion 5-fluorouracil, and leucovorin in patients with locally advanced upper-abdominal gastrointestinal cancer. METHODS AND MATERIALS: Patients with locally advanced or locally recurrent gastric, pancreatic, or extrapelvic colon cancer were eligible for this study. Radiation therapy consisted of 45 Gy in 25 fractions to the tumor and regional lymph nodes, followed by 5.4-9 Gy in three to five fractions to the tumor. Treatment with leucovorin, 10 mg orally daily, and continuous infusion 5-fluorouracil was initiated on the first day of radiation therapy. 5-Fluorouracil was administered at an initial daily dose of 125 mg/m2, with dose escalation planned in 25-mg increments, depending on patient tolerance. RESULTS: Twenty-one evaluable patients participated in this study. Six were treated at the initial daily 5-fluorouracil dose of 125 mg/m2. One patient experienced Grade 4 anorexia and nausea. No other Grade > or = 3 toxicity was observed at this dose. Fifteen evaluable patients were entered at a planned 5-fluorouracil dose of 150 mg/m2 daily; 6 of them experienced Grade 3 toxicity, and none experienced Grade > or = 4 toxicity. Grade 3 toxicities and the number of patients who developed each were: vomiting (three patients); nausea (two patients); diarrhea (two patients); and skin toxicity, hand-foot syndrome, catheter-related infection, and stomatitis in one patient each. Four of the six patients who experienced Grade 3 toxicity developed more than one type of Grade 3 toxicity. CONCLUSIONS: In patients with upper-abdominal gastrointestinal cancer, continuous infusion 5-fluorouracil (150 mg/m2 daily), leucovorin (10 mg orally daily), and radiation therapy (50-54 Gy) resulted in a 40% rate of severe toxicity but no life-threatening toxicity. This clinical trial excludes, with 90% confidence, a 20% risk of Grade 4 toxicity with this combination. The 40% rate of severe toxicity suggests that this combination of agents is near the maximal tolerated dose.

Antidotes↗
PubMed1999

Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer.

The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment-induced mucositis significantly increased with (6S)-folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.

Aged↗
PubMed2002

Clinical and economic benefits of irinotecan in combination with 5-fluorouracil and folinic acid as first line treatment of metastatic colorectal cancer.

The combination of irinotecan plus 5-fluorouracil and folinic acid has clinical and survival benefits over 5-fluorouracil and folinic acid alone in the setting of first line treatment of metastatic colorectal cancer. The aim of this cost-effectiveness analysis was to compare the economic implications, from a UK health commissioner perspective, of the two treatment arms (de Gramont regimen) in this setting. Resource utilisation data collected prospectively during the study were used as a basis for estimating cumulative drug dosage, chemotherapy administration, and treatment of complications during first line therapy. Resource utilisation associated with further chemotherapy in patients who had progressed during the study was derived from a retrospective case note review. Drug acquisition costs were derived from the British National Formulary (September, 2001) and unit costs for clinical consultation and services were taken from the latest relevant cost database. Cumulative costs per patient associated with further chemotherapy were lower in the irinotecan plus 5-fluorouracil and folinic acid treatment arm. Based on incremental costs per life-year gained of 14 794 pounds sterling, the combination of irinotecan plus 5-fluorouracil and folinic acid can be considered cost-effective by commonly accepted criteria compared with 5-fluorouracil and folinic acid alone. Thus, clinical and economic data demonstrate that irinotecan, either in combination with irinotecan plus 5-fluorouracil and folinic acid in the first line setting or as monotherapy in the second line setting, has a major role in the management of metastatic colorectal cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1987

Absorption of 5-fluorouracil and related pyrimidines in rat small intestine.

The transport of 5-fluorouracil, uracil and thymine has been studied with isolated jejunal loops of rat small intestine. High performance liquid chromatography was used to identify the pyrimidines and measure their concentrations. When the lumen of the intestine was perfused with 5-fluorouracil or uracil at 0.1 mmol/l or 0.2 mmol/l, the concentration in the serosal secretions was significantly higher than that in the lumen. For thymine the serosal concentration exceeded that in the lumen only at 0.1 mmol/l. Analysis of the mucosal tissue water at the end of the perfusion demonstrated that when the intestinal lumen was perfused with any one of the three pyrimidines at 0.1 mmol/l or 0.2 mmol/l the concentration within the tissue was significantly above that in the lumen. After an initial lag period linear rates of transport from the lumen to the serosal secretions were obtained for all three pyrimidines over a 10-fold concentration range from 0.1 mmol/l to 1 mmol/l. Uracil and thymine inhibited the transmural transport of 5-fluorouracil. The transport of 5-fluorouracil was also studied with a vascularly perfused preparation of rat small intestine. At 0.1 mmol/l the rate of transmural transport of the drug in this preparation was substantially higher than in the jejunal loops. This difference was eliminated by adding 5-fluorouracil to the vascular perfusate, suggesting that the higher transport rate in the vascularly perfused preparation was due to the lower serosal drug concentrations in the mesenteric circulation of the perfused intestine. At a concentration of 5 mmol/l 5-fluorouracil inhibited water transport in the isolated loops and transmural D-galactose transport in the vascular perfusions.

Animals↗
PubMed1992

Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.

BACKGROUND: The combination of streptozocin and fluorouracil has become the standard therapy for advanced islet-cell carcinoma. However, doxorubicin has also been shown to be active against this type of tumor, as has chlorozotocin, a drug that is structurally similar to streptozocin but less frequently causes vomiting. METHODS: In this multicenter trial, we randomly assigned 105 patients with advanced islet-cell carcinoma to receive one of three treatment regimens: streptozocin plus fluorouracil, streptozocin plus doxorubicin, or chlorozotocin alone. The 31 patients in whom the disease did not respond to treatment were crossed over to chlorozotocin alone or to one of the combination regimens. RESULTS: Streptozocin plus doxorubicin was superior to streptozocin plus fluorouracil in terms of the rate of tumor regression, measured objectively (69 percent vs. 45 percent, P = 0.05), and the length of time to tumor progression (median, 20 vs. 6.9 months; P = 0.001). Streptozocin plus doxorubicin also had a significant advantage in terms of survival (median, 2.2 vs. 1.4 years; P = 0.004) that was accentuated when we considered long-term survival (greater than 2 years). Chlorozotocin alone produced a 30 percent regression rate, with the length of time to tumor progression and the survival time equivalent to those observed with streptozocin plus fluorouracil. Crossover therapy after the failure of either chlorozotocin alone or one of the combination regimens produced an overall response rate of only 17 percent, and the responses were transient. Toxic reactions to all regimens included vomiting, which was least severe with chlorozotocin; hematologic depression; and, with long-term therapy, renal insufficiency. CONCLUSIONS: The combination of streptozocin and doxorubicin is superior to the current standard regimen of streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozocin plus fluorouracil, but it produces fewer gastrointestinal side effects than the regimens containing streptozocin. It therefore merits study as a constituent of combination drug regimens.

Adenoma, Islet Cell↗