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PubMed2003

Enhancement of antitumor effects of 5-fluorouracil combined with ultrasound on Ehrlich ascites tumor in vivo.

To evaluate the role of ultrasonic waves in enhancing the effect of 5-fluorouracil (5-FU) as anticancer drug, tumor growth, cell ultrastructure and temperature rises of ascites Ehrlich tumor implanted in mice were investigated at a frequency of 0.8 MHz. Different conditions of ultrasonic intensity (1, 2 and 3 W/cm(2)), sonocation time (1, 3 and 5 min) and waveform (continuous and pulsed) were studied. A total of 10 mg/kg body weight of 5-FU was IV injected into the mice bearing Ehrlich tumors on days of 1, 3, 5, 8, 10 and 12 of therapy. After 24 h of each injection with 5-FU, tumor sites were sonocated at room temperature of 22 degrees C. Tumor volumes were monitored by using ultrasonic imaging system during treatment just before each 5-FU injection, and on the 15th day of treatment. Density and ultrasonic attenuation of excised tumor tissues were measured in vitro and used to estimate the temperature rises due to ultrasonic absorption. Density and attenuation coefficients of excised tumor tissues were found to be dependent on the treatment regimen. The estimated rate of temperature rise and equilibrium temperature, and the characteristic time to reach equilibrium are given for each group. Results obtained indicate that tumor growth decreases with increasing of ultrasonic intensity and sonocation time. Tumor growth was delayed 4 to 6 days by combined treatment of 5- fluorouracil and ultrasound (US). Ultrastructure investigations of tumor cells showed severe damage in cytoplasmic organelles and cytoplasmic vacuoles that increased with increasing ultrasonic intensity and sonocation time. This damage appears as prominent crowded vacuoles among swollen ruptured organelles, chromatin fragments and severe increase in numbers of pyknotic and apoptotic cells.

Animals↗
PubMed2004

Successful transfer of frozen-thawed embryos obtained after subtotal colectomy for colorectal cancer and before fluorouracil-based chemotherapy.

Background. Fertility preservation is applied to patients with cancer who may be rendered sterile from chemotherapy or radiotherapy. Fluorouracil is considered as having almost no effect on human reproductive function, although clinical data defining infertility risk is negligible. Case. Controlled ovarian stimulation, in vitro fertilization (IVF), and embryo freezing were performed before fluorouracil-based chemotherapy in a 28-year-old woman who underwent subtotal colectomy for colorectal cancer (CRC). Three years later, when the clinical and hormonal analysis confirmed ovarian failure, two thawed embryos were transferred to the uterus. She gave birth at term to a 3200g infant. Discussion. Women with good prognosis who wish to bear children in the future should be offered fertility preservation options before chemotherapy, even if the likelihood of permanent ovarian failure appears to be negligible.

Adult↗
PubMed1993

Late complications after glaucoma filtering surgery with adjunctive 5-fluorouracil.

We studied 105 patients (105 eyes) operated on for glaucoma with adjunctive fluorouracil, who were followed up for 12 to 48 months (mean, 34.6 +/- 12.9 months). Fifty eyes that had previous glaucoma or cataract extraction or had inflammatory glaucoma had a high risk for postoperative scarring (high-risk group), and 55 eyes had glaucoma surgery as an initial procedure (initial surgery group). An intraocular pressure of 20 mm Hg or less, with or without hypotensive medications, was found in 42 eyes in the high-risk group (84.0%) and in 53 of the eyes in the initial surgery group (96.4%). Of the 105 eyes, an intraocular pressure of 12 mm Hg or less without medication was achieved in 17 eyes in the high-risk group (34.0%) and in 35 eyes in the initial surgery group (63.6%). Late complications in both groups were as follows: endophthalmitis in four eyes (3.8%) (two of the infected blebs were located superiorly and two inferiorly), transient leaking bleb in two eyes (1.9%), hypotony of an extended period with 180 to 360 degrees of filtration in three eyes (2.9%), giant bleb extending over the cornea in two eyes (1.9%), and a transient, mild iridocyclitis in nine eyes (8.6%). Thus, adjunctive fluorouracil after filtering surgery may entail various, mainly bleb-related, late side effects and complications.

Adolescent↗
PubMed1992

Risk factors for suprachoroidal hemorrhage after filtering surgery. The Fluorouracil Filtering Surgery Study Group.

In the Fluorouracil Filtering Surgery Study, ten of 162 eyes (6.2%) that had undergone previous cataract extraction developed a nonexpulsive suprachoroidal hemorrhage after filtering surgery. Of the previously reported risk factors, including age, myopia, history of vitrectomy, history of 5-fluorouracil injections, postoperative hypotony, and high preoperative intraocular pressure, only high preoperative intraocular pressure was statistically significant (P = .002). The risk of suprachoroidal hemorrhage was strongly associated with the level of the preoperative intraocular pressure. None of the 63 patients with a preoperative intraocular pressure less than 30 mm Hg, three of the 47 patients (6%) with a preoperative intraocular pressure between 30 and 39 mm Hg, four of the 36 patients (11%) with a preoperative intraocular pressure between 40 and 49 mm Hg, two of the 12 patients (17%) with a preoperative intraocular pressure between 50 and 59 mm Hg, and one of four patients with an intraocular pressure more than 60 mm Hg developed a suprachoroidal hemorrhage. Because the preoperative intraocular pressure was highly correlated with the difference between the preoperative and the postoperative intraocular pressure, it was not possible to distinguish which factor was clinically more important.

Aged↗
PubMed1996

Alternating floxuridine and 5-fluorouracil hepatic arterial chemotherapy for colorectal liver metastases minimizes biliary toxicity.

BACKGROUND: The goals of this study of a hepatic arterial infusion (HAI) regimen of alternating floxuridine and 5-fluorouracil were to evaluate the treatment-related toxic effects, the antitumor response rate, and patient survival. METHODS: Fifty-seven consecutive patients were treated with implanted HAI pumps and received a regimen of alternating floxuridine (0.1 mg/kg/day continuous HAI for 7 days) followed by a weekly HAI pump bolus of 5-fluorouracil (15 mg/kg for 3 weeks). Any changes in treatment plan because of toxicity, antitumor response, and survival were recorded. RESULTS: Thirty-one (54.4%) patients responded to this HAI regimen; 14 (24.5% )patients had stable disease, and 12 (21.1%) progressed during treatment. Responders or patients with stable disease had a significantly (P < 0.05) improved survival rate (19 months median) compared with patients in whom disease progressed (12 months median). Two (3.5%) patients developed biliary sclerosis and 12 (21.1%) had mild transient liver function abnormalities. The liver alone or in combination with another area was the site of first progression of disease in 40 (70.2%) patients. CONCLUSIONS: This regimen had reversible or no hepatobiliary toxicity in more than 95% of patients. Tumor reduction or stabilization of disease was observed in 79% of the patients, who had a median survival of 19 months. Reduced toxicity and more effective chemotherapeutic regimens may increase the likelihood of survival after HAI chemotherapy for unresectable colorectal liver metastases.

Adult↗
PubMed2002

Development and characterization of a monoclonal antibody with cross-reactivity towards uracil and thymine, and its potential use in screening patients treated with 5-fluorouracil for possible risks.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in catabolism of pyrimidines including 5-fluorouracil. There have been efforts to isolate a monoclonal antibody that will bind selectively to pyrimidine and can be used to measure the concentration of pyrimidine in blood and/or in urine that may reflect the activity of dihydropyrimidine dehydrogenase. However, the monoclonal antibodies selective to pyrimidine have not been available. METHODS: Using 1-carboxymethyl-uracil as a hapten, in which steric conformation of uracil is thought to be well maintained, extensive screening was done to isolate a monoclonal antibody specific to uracil. RESULTS: We established the first monoclonal antibody that reacted with uracil and thymine but not with pseudouridine, dihydrouracil, dihydrothymine, cytosine, uridine, or N-carbamyl-beta-alanine at the concentration of 100 microg/ml. CONCLUSIONS: The monoclonal antibody can be used to develop a simple screening assay for patients with dihydropyrimidine dehydrogenase deficiency. This may increase the safety of 5-fluorouracil treatment.

Animals↗
PubMed1979

Gas-liquid chromatography of some alkyl derivatives of 5-fluorouracil.

Various procedures for converting 5-fluorouracil into its methyl, butyl and hexyl derivatives are described. Structures were established as the N,N'-dialkyl derivatives using mass spectrometry or combined gas-liquid chromatography-mass spectrometry. The reaction conditions, i.e., the amount of derivatization reagents and reaction time, were optimized. Gas-liquid chromatographic characteristics of the derivatives were investigated on different stationary liquid phases, and 2% or 3% SP-2250, 5% XE-60 and 5% OV-1 were found to be superior. With 5-chlorouracil as the internal standard a linear response for the various derivatives was observed in the microgram range. The applicability of the different dialkyl derivatives in the measurement of 5-fluorouracil in biological materials is discussed.

Alkylation↗
PubMed2003

Determination of uracil in 5-fluorouracil substance by high-performance liquid chromatography.

Separation of 5-fluorouracil and uracil in chromatographic systems consisting of a silica column as a stationary phase and ethyl acetate or ethyl acetate partially saturated with water as a mobile phase has been studied. The results indicated that when saturation of ethyl acetate with water was chosen to reach more than 60%, such mobile phases [e.g., 2.4% (v/v) water in ethyl acetate] are useful in determining uracil in 5-fluorouracil substances.

Chromatography, High Pressure Liquid↗
PubMed2003

Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation in resectable esophageal carcinoma: a phase I report.

PURPOSE: To assess the benefits of aggressive chemoradiation therapy followed by surgery in resectable esophageal carcinoma. METHOD: Twenty-nine patients with resectable carcinoma were treated with 60 Gy of radiation (2 Gy daily for 6 weeks) and concurrent chemotherapy consisting of continuous infusion of 5-fluorouracil (200-225 mg/m(2)/d), paclitaxel (25, 40, 50, or 60 mg/m(2)) weekly over 1 hour, and cisplatin (25 mg/m(2)) weekly immediately following paclitaxel throughout radiation. Patients received either 4 cycles of postoperative paclitaxel 175 mg/m(2) over 3 hours and cisplatin 75 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) over 3 hours and cisplatin 75 mg/m(2) every 3 weeks prior to the initiation of chemoradiation. After induction therapy and restaging, esophagectomy was performed 4 to 6 weeks later. RESULTS: Twenty-seven patients were eligible for study (26 men, 23 with adenocarcinoma). Median age was 58 years (range 30-73). The maximum tolerated dose combination was paclitaxel 50 mg/m(2) over 1 hour weekly, cisplatin 25 mg/m(2) over 1 hour weekly, 5-fluorouracil 200 mg/m(2)/d by continuous infusion throughout radiotherapy and radiation to 60 Gy. Twenty-two patients completed therapy and underwent surgical resection. Four patients had complete pathological responses and 18 had partial responses with no mortality. The commonest dose-limiting toxicity was mucositis and esophagitis (n = 7). Median follow-up of 27 patients was 150 weeks (range 7-303). At 2-year follow-up 16/27 (59%) were alive and 15/27 (56%) were free of disease. At 4-year follow-up 12/27 (44%) were alive and free of disease. Median follow-up of 22 patients undergoing esophagectomy was 205 weeks (range 26-303). At 4-year follow-up 10/22 (45%) were alive and free of disease. For the 18 patients treated at or above the maximum tolerated dose, median follow-up was 151 weeks (range 35-206) and at 3-year follow-up 9/18 (50%) were alive and free of disease. CONCLUSION: Aggressive combined modality therapy of esophageal carcinoma was associated with excellent long-term survival in this phase I trial.

Adenocarcinoma↗
PubMed1992

Phase II study of interferon-alpha and chemotherapy (5-fluorouracil and mitomycin C) in metastatic renal cell cancer.

A total of 49 patients with metastatic renal cell cancer underwent recombinant interferon-alpha 2a therapy combined with chemotherapy. Before therapy the patients without nephrectomy underwent angioinfarction of the primary renal tumor. Combined treatment included interferon at 5 x 10(6) units per m.2 intramuscularly daily, 5-fluorouracil at 750 mg./m.2 daily by continuous infusion intravenously (days 1 to 5) and mitomycin C at 5 mg./m.2 per day intravenously (days 1 and 2) repeated every 28 days. Of the patients 17 (35%, 95% confidence interval 22 to 49%) responded, and all 17 had partial remission that lasted a median of 7.1 months (range 4.2 to 20.9+ months). Response rate differed by metastatic sites: lung 46% (18 of 39 patients), lymph nodes 46% (6 of 13), mediastinum 20% (2 of 10) and liver 18% (2 of 11). Grade 3 to 4 toxicity (World Health Organization) included neutropenia (79% of the patients), thrombocytopenia (45%), stomatitis (34%), diarrhea (8%), nausea (18%) and central nervous system disorders (18%). The overall 35% response rate suggests that the combination of interferon-alpha 2a, 5-fluorouracil and mitomycin C is synergistic. Future studies are needed to confirm this finding and to assess the role of mitomycin C.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Cisplatin and 5-fluorouracil in advanced cancer of the penis.

A total of 8 patients with advanced squamous cell carcinoma of the penis (Jackson stages III and IV) received chemotherapy with 100 mg./m2. cisplatin intravenously on day 1 and a 24-hour infusion of 1,000 mg./m.2 5-fluorouracil on days 1 to 5. Of the patients 2 (25%) achieved a partial response: 1 required a further operation and 1 required surgery with radiotherapy to achieve a complete response. These 2 patients were disease-free at 32+ and 57+ months. Nonresponders had a survival range of 2+ to 28 months after chemotherapy. Nausea and vomiting were the most frequent side effects of chemotherapy. Chemotherapy-related increase in serum creatinine occurred in 3 patients. Two patients had septicemia and 1 complained of tinnitus. Poor tolerability especially in the elderly was the main reason for discontinuing chemotherapy. The combination of cisplatin and 5-fluorouracil may have a role in the management of advanced penile cancer together with surgery and radiotherapy.

Adult↗
PubMed1984

Intravesical high dose 5-fluorouracil instillations combined with allopurinol--a therapeutic alternative in the treatment of multiple bladder tumors.

Chemical cystitis and systemic toxic effects limit the therapeutic use of intravesical cytotoxic agents against bladder tumors. In our series 1,000 mg. 5-fluorouracil could be instilled 2 hours daily, 5 days per week for 5 weeks if 100 mg. allopurinol were given 3 times daily simultaneously. After 6 weeks all patients were macroscopically free of tumors. Another instillation was performed because of recurrences within 6 months in 3 patients. This preliminary report of 5 patients with multiple superficial transitional cell bladder tumors shows that a combined treatment of high dose 5-fluorouracil instillation and simultaneous oral allopurinol will abolish temporarily all tumor tissue without signs of general absorption or chemical cystitis. The observation time is too short to predict definitive cure.

Allopurinol↗
PubMed1998

Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group, the Gruppo Interdisciplinare Valutazione Interventi in Oncologia, and the Japanese Foundation for Cancer Research.

BACKGROUND: There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). METHODS: 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. FINDINGS: 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% Cl for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). INTERPRETATION: PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

Aged↗
PubMed1998

Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer.

BACKGROUND: In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial. METHODS: Patients with proven metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil, were randomly assigned either 300-350 mg/m2 irinotecan every 3 weeks with supportive care or supportive care alone, in a 2:1 ratio. FINDINGS: 189 patients were allocated irinotecan and supportive care and 90 supportive care alone. The mean age of the participants was 58.8 years; 181 (65%) were men and 98 (35%) were women. WHO performance status was 0 in 79 (42%) patients, 1 in 77 (41%) patients, and 2 in 32 (17%) patients. Tumour-related symptoms were present in 134 (71%) patients and weight loss of more than 5% was seen in 15 (8%) patients. With a median follow-up of 13 months, the overall survival was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. The survival benefit, adjusted for prognostic factors in a multivariate analysis, remained significant (p=0.001). Survival without performance-status deterioration (p=0.0001), without weight loss of more than 5% (p=0.018), and pain-free survival (p=0.003) were significantly better in the patients given irinotecan. In a quality-of-life analysis, all significant differences, except on diarrhoea score, were in favour of the irinotecan group. INTERPRETATION: Our study shows that despite the side-effects of treatment, patients who have metastatic colorectal cancer, and for whom fluorouracil has failed, have a longer survival, fewer tumour-related symptoms, and a better quality of life when treated with irinotecan than with supportive care alone.

Adult↗
PubMed2000

Trabeculectomy with intraoperative mitomycin C versus 5-fluorouracil. Prospective randomized clinical trial.

OBJECTIVE: To evaluate the relative efficacy and safety of 5-fluorouracil (5-FU) and mitomycin C (MMC) when used as adjuncts with primary trabeculectomy in eyes not at high risk for failure. DESIGN: Prospective multicenter, randomized clinical trial. PARTICIPANTS: One hundred thirteen patients with primary open-angle, pseudoexfoliative, pigmentary, or angle-closure glaucoma undergoing primary trabeculectomy were recruited. METHODS: One eye of each patient was randomized to receive either 5-FU (50 mg/ml for 5 minutes) or MMC (0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: Intraocular pressure (IOP), visual acuity, complications, and interventions were documented at fixed intervals after surgery. The study also examined progression of visual field loss, long-term complications, and bleb appearance 3 years after surgery. RESULTS: Of the 108 patients with complete perioperative information, 54 eyes received 5-FU and 54 received MMC. The proportion of patients reaching different predefined target IOPs after surgery was slightly higher in the MMC group than in the 5-FU group. This difference was less than 25%, which would have been necessary to achieve statistical significance with a power of 0.8 and the sample size used. Likewise, there was no statistically significant difference between the groups with regard to mean preoperative IOP, complications, or interventions. Mean postoperative follow-up was 309 and 330 days in the 5-FU and MMC groups, respectively (P = 0.593). CONCLUSIONS: 5-Fluorouracil and MMC were found to be equally safe and effective adjuncts to primary trabeculectomy in the short- and medium-term postoperative periods.

Aged↗
PubMed2002

Squamous metaplasia of the canaliculi associated with 5-fluorouracil: a clinicopathologic case report.

OBJECTIVE: To illustrate a newly recognized histopathologic change in a patient with canalicular obstruction after weekly administration of 5-fluorouracil for colon cancer. DESIGN: Interventional case report. METHODS: A full-thickness section of canaliculus was obtained during surgical repair. MAIN OUTCOME MEASURE: Histopathologic changes in the specimen. RESULTS: The prominent histologic feature of the canalicular specimen was severe squamous metaplasia with narrowing of the lumen. CONCLUSION: Canalicular obstruction may follow systemic use of 5-fluorouracil due to squamous metaplasia.

Aged↗
PubMed1992

Inhibition of corneal epithelial wound healing. A comparative study of mitomycin C and 5-fluorouracil.

PURPOSE: The purpose of this study is to assess the influence of the antiproliferative agents, 5-fluorouracil (5-FU) and mitomycin C (MMC), on the intact corneal epithelium and on epithelial wound healing in the rabbit cornea. METHODS: Using an eye cup made of polymethylmethacrylate, the intact rabbit corneas were bathed for 5 or 15 minutes with either MMC (in concentrations of 0.0016%, 0.008%, 0.04%, and 0.2%) or 5-FU (in concentrations of 1% and 5%). The same concentrations of MMC or 5-FU were applied to the cornea with the eye cup in which epithelial cells were mechanically removed. The contralateral fellow eyes, which were bathed in balanced salt solution in the eye cup, had the cornea intact or mechanically abraded and served as controls. Five to six animals were used only once for each concentration of MMC or 5-FU. RESULTS: Neither MMC nor 5-FU caused any discernible changes in the intact cornea of any of the eyes. The epithelial healing was retarded by mitomycin in a dose-related manner, and ID50 was calculated to be 0.06%. Five-fluorouracil 5% significantly delayed epithelial healing, but 1% failed to do so. Mitomycin C was estimated to be at least 125 times as potent as 5-FU in inhibiting corneal epithelial healing. CONCLUSION: These results indicate that particular care should be taken to minimize corneal contact with MMC in the clinical setting, particularly when epithelial defects are present.

Animals↗
PubMed1994

5-Fluorouracil in initial trabeculectomy. A prospective, randomized, multicenter study.

PURPOSE: Postoperative subconjunctival 5-fluorouracil (5-FU) injections increase the success of filtration surgery in eyes with prior filtration failure or cataract removal and in eyes with secondary glaucoma. The authors evaluate the safety and benefit of adjunctive 5-FU in eyes undergoing initial trabeculectomy. METHODS: Patients with phakic, uncontrolled, open-angle glaucoma who were undergoing initial trabeculectomy were prospectively assigned to the 5-FU group on the first postoperative day. Patients in this group received five 5-mg injections during 2 weeks after surgery. Patients in the control group received no injections. RESULTS: Preoperative intraocular pressure (IOP) and number of antiglaucoma medications were similar in the 5-FU (n = 32) and control (n = 30) groups. Transient superficial punctate keratopathy was the only postoperative complication that occurred more frequently (P < 0.05) in the 5-FU (14 eyes) than in the control eyes (3 eyes). Patients were followed for a minimum of 1 year or until a study endpoint was reached: IOP of 21 mmHg or greater with maximum medical therapy (2 5-FU eyes and 8 control eyes; P < 0.03) or cataract removal after filtration (5 treated and 3 control eyes). At last follow-up (mean, > 20 months), IOP and the number of antiglaucoma medications were significantly lower (P < 0.02) in the 5-FU eyes (IOP, 12.0 +/- 1.3 mmHg; medications, 0.2 +/- 0.1) than in the control eyes (IOP, 16.8 +/- 1.3 mmHg; medications, 0.8 +/- 0.2). Intraocular pressure was 20 mmHg or lower in 94% of 5-FU eyes and in 73% of control eyes (P < 0.03) and 16 mmHg or lower in 84% of 5-FU eyes and in 57% of control eyes (P < 0.02). CONCLUSIONS: Adjunctive 5-fluorouracil increases the rate of success, decreases the level of postoperative IOP, and reduces the need for postoperative antiglaucoma medication in eyes with open-angle glaucoma undergoing initial trabeculectomy.

Aged↗