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PubMed1989

Evidence of a new metabolic pathway of 5-fluorouracil in Escherichia coli from in vivo 19F-NMR spectroscopy.

Two distinct metabolic pathways of 5-fluorouracil are proposed in Escherichia coli. The first metabolic pathway is a reductive degradation with the formation of dihydrofluorouracil as the first metabolite. The second metabolic pathway is shown to be a hydroxylating degradation, possibly with the formation of 5-hydro-6-hydroxy-5-fluorouracil as the first metabolite. The metabolites of both pathways undergo subsequent hydrolytic degradation with fluoride ion as the common final product. The chemical structures of these metabolites were partially identified by 19F-NMR. The results show a close resemblance between these two metabolic pathways with in vivo pyrimidine biodegradation. The reductive degradation has been proposed by several laboratories, whereas the hydroxy degradation has not been reported before. Both the reductive and hydroxy pathways are demonstrated in this report, to be independent reactions.

Escherichia coli↗
PubMed1995

Myocardial ischemia induced by topical use of 5-fluorouracil.

An 85-year-old woman, with known stable angina pectoris, was prescribed 5-fluorouracil cream to treat a small basal cell carcinoma on the forehead. Half an hour after application the patient developed her typical ischemic pain which persisted for 2 hours. Rechallenge, during hospitalization, resulted in recurrence of symptoms that were effectively controlled with sublingual isosorbide dinitrate. Prophylactic therapy with nitroglycerin patch enabled further use of the 5-fluorouracil cream for the next month.

Administration, Topical↗
PubMed1995

Concurrent 5-fluorouracil, mitomycin C and irradiation in locally advanced cervix cancer.

We reviewed 177 patients treated with radical radiotherapy for locally advanced (FIGO stages IIB, IIIA, IIIB) cervix cancer between January 1979 and December 1989. The radiotherapy was given by external beam treatment to the pelvis and by an intracavitary caesium insertion. Ninety-three patients also received chemotherapy which consisted of infusional 5-fluorouracil during the first and last weeks of the external beam component of the radiotherapy, combined with bolus mitomycin C (group A, 64 patients) or without mitomycin C (group B, 29 patients). These groups were compared with patients treated by radiotherapy alone (group C, 84 patients). The median follow-up was 7.2 years. The median survival time for all patients was 47 months, but was significantly higher (87 months, p = 0.004) for group A. Rates of relapse-free survival and local control were also higher in group A. Toxicity was assessed in detail using the Franco-Italian glossary. There was a relatively high rate of complications, particularly in group A, with 36% of patients having grade 3 or 4 complications. This increase in toxicity persisted through all follow-up time intervals. Patients in group B also demonstrated a higher rate of toxicity than group C, but this increase was limited to the first 6 months of follow-up. The use of mitomycin C in addition to radiotherapy and 5-fluorouracil should be regarded with caution, as other studies have also shown that toxicity is increased, but without improvements in survival.

Adenocarcinoma↗
PubMed1994

Cisplatin-5-fluorouracil in small cell lung cancer. A phase II study in 109 patients.

One hundred nine previously untreated patients with small cell lung cancer were treated for five consecutive days with 20 mg/m2/day of cisplatin and 600 mg/m2/day of 5-fluorouracil. One cycle of chemotherapy was administered every three weeks. The patients received a median number of three cycles. Then they were transferred to CAE chemotherapy. A 77% overall response rate (95% confidence interval of 0.70-0.85) was observed after initial cisplatin-5FU treatment. Twenty-three complete responses (21%) and 62 partial responses (56%) were obtained. In cerebral metastases the response rate was high at 91% (21 out of 23), with 43% complete responses. In the limited forms, statistical survival at 1 year was 25%. A Grade 3-4 thrombocytopaenia was observed in 10 patients (9%) and a Grade 2-3 leukopaenia in four patients. Three patients suffered from a Grade 2 cardiac toxicity. The cisplatin-5-fluorouracil combination demonstrates promising initial response rate in small cell lung cancers. Its main interest is in its important action on cerebral metastases and its moderate haematological toxicity.

Adult↗
PubMed1991

Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses.

Ten patients completed a weekly pulse dosing regimen for topical 5-fluorouracil therapy for multiple facial actinic keratoses. The method cleared an average of 98% of the lesions, without the severe irritation usually caused by the conventional, daily dosing regimen. Nine patients described the therapy as comfortable. Local irritation was limited to erythema. None of the patients suffered disruption in their social or business lives because of altered appearance. Patients had an average of 6.7 weeks of treatment and applied the medication 1 to 2 days per week; significant remissions were achieved. The longest available follow-up is with six patients who at 9 months remained 86% clear of lesions. This new method offers a significant advance in topical 5-fluorouracil therapy by reducing irritation to an acceptable level while maintaining efficacy.

Administration, Cutaneous↗
PubMed1993

Combination chemotherapy with 5-fluorouracil, folinic acid, and alpha-interferon producing histologic features of graft-versus-host disease.

Fluorouracil is a common cause of acral erythema and a variety of pigmentary anomalies. These conditions are believed to be the result of a direct toxic effect or a graft-versus-host-like reaction. We describe two cases in which an erythematous eruption that evolved into hyperpigmented, hyperkeratotic lesions developed in two patients who were receiving combination chemotherapy (5-fluorouracil, folinic acid, and alpha-interferon). The histologic features included apoptotic keratinocytes with exocytosis of mononuclear cells, some showing satellitosis, and hydropic change of the basal cell layer with an interface dermatitis that was most marked within the distal eccrine duct and acrosyringium. Clinicopathologic correlation suggests that the eruption was primarily caused by involvement of the sweat glands and hair follicles. Although a direct toxic effect may play some role, the histologic features suggest that the dominant mechanism is a graft-versus-host-like or host-versus-altered-host-type reaction.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

An EORTC Gastrointestinal Group phase II evaluation of epirubicin combined with 5-fluorouracil in advanced adenocarcinoma of the pancreas.

The EORTC Gastrointestinal Group has conducted a phase II trial in 47 patients with locally advanced or metastatic adenocarcinoma of the pancreas with epirubicin 90 mg/m2 intravenously on day 1 in combination with 5-fluorouracil 500 mg/m2 in a 2 hr infusion day 1-4, every 4 weeks. Of 43 evaluable patients there were six early deaths due to tumour progression and one due to a cerebrovascular accident. There were six partial responses for a response rate of 14% including early deaths. The median survival for all patients was 4 months. It is concluded that the addition of 5-fluorouracil to epirubicin does not appear to enhance the therapeutic results of epirubicin alone.

Adenocarcinoma↗
PubMed1988

High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer.

An enhanced antineoplastic effect of 5-fluorouracil in patients with advanced colorectal cancer has been produced either by combination with folinic acid or administration by continuous infusion. Thirty-seven patients with advanced measurable colorectal cancer received high-dose folinic acid (LV 200 mg/m2) followed by 5-fluorouracil i.v. bolus (300 mg/m2) and continuous infusion (300 mg/m2) on days 1 and 2 then 14 and 15 every 4 weeks. In the absence of toxicity, 5-FU was increased to 400 mg/m2 i.v. bolus and continuous infusion at course 2 and to 500 mg/m2 at course 3 and from course 4 maintained at 500 mg/m2. Responses were: complete responses: 1 (2.7%), partial responses: 19 (51.4%), no change: 8 (21.6%) and progressive disease: 9 (24.3%). CEA decrease was correlated with response. Median duration of response was 11 months. Median survival was 18 months, 21% of the patients were alive at 2 years. Toxicity was low, with diarrhea in 17% and nausea in 11.5% of the patients. LV-5-FU bolus and continuous infusion is safe and has definite activity in metastatic colorectal cancer.

Adenocarcinoma↗
PubMed1991

Phase II intravenous study of epirubicin with 5-fluorouracil in patients with advanced hepatocellular carcinoma.

Between August 1986 and September 1990, 22 previously untreated non-cirrhotic patients with measurable unresectable primary liver cancer were treated every 4 weeks with a combination of epirubicin and 5-fluorouracil. The dose of epirubicin was escalated; the starting dose was 40 mg/m2, the second dose was 50 mg/m2 and thereafter 60 mg/m2 during subsequent cycles. The dose of 5-fluorouracil was always 800 mg/m2. Objective response rate was 14%. Most of the patients experienced only mild haematological toxicity, and no other dose limiting toxicity was observed. Nonetheless, increasing the dose would probably not have increased the response rate.

Adolescent↗
PubMed1996

Title aggregation patterns of argyrophilic nucleolar organizer regions induced by 5-fluorouracil in the nuclei of MCF-7 human breast cancer cells.

The effects of tamoxifen and 5-fluorouracil (5-FU) on the patterns of argyrophilic nucleolar organizer regions (AgNORs) in MCF7 human breast cancer cells were studied. Tamoxifen and 5-FU both inhibited the growth of MCF-7 cells by 18% by day 3 of culture, but each had different effects on the AgNORs. Whereas no significant changes were induced by tamoxifen, effects on the AgNORs of MCF-7 cells by 5-FU were dramatic: 5-FU treatment changed the pattern of AgNORs, reducing the number of satellites by aggregation, typically to a single aggregation around nucleoli in a sphenoidal fashion. We named these morphological changes: fluorouracil induced AgNOR aggregations (FAA). Following treatment with 500 ng/ml 5-FU, FAA developed rapidly. AgNORs forming two or three aggregates in 24% (6 h), 24% (12 h), 40% (24 h) and 34% (48 h) of cells, compared to a control rate of 14%. Single large aggregate was rarely found in untreated cultures but after 6, 12, 24 and 48 h treatment with 500 ng/ml 5-FU, AgNORs had formed a single aggregate in 6, 8, 16 and 22% of cells, respectively. FAA were observed at a concentration of 100 ng/ml 5-FU; 48 h treatment resulted in cells in which two or three aggregates were increased by 24% and single aggregate by 16%. These large single aggregates were larger than nucleoli stained by Papanicolau staining.

Antimetabolites, Antineoplastic↗
PubMed1996

The effects of 5-fluorouracil and doxorubicin on expression of human immunodeficiency virus type 1 long terminal repeat.

Previous work by many groups has documented induction of the human immunodeficiency virus (HIV) long terminal repeat (LTR) following exposure of cells to ultraviolet light and other DNA damaging agents. Our experiments set out to determine the relative activation or repression of the HIV-LTR in response to two classes of chemotherapeutic agents: Doxorubicin is a DNA damage-inducing agent, and 5-fluorouracil has an antimetabolic mode of action. Using HeLa cells stably transfected with a construct in which HIV-LTR drives expression of the chloramphenicol acetyl transferase reporter gene, we demonstrated an up to ten-fold induction following doxorubicin treatment at 24 h post-treatment. This induction was repressed by treatment with salicylic acid, suggesting a role for prostaglandin/cyclo-oxygenase pathways and/or NF-kappa B in the inductive response. Induction by 5-fluorouracil, in contrast, was more modest (two-fold at most) though it was consistently elevated over controls.

Antibiotics, Antineoplastic↗
PubMed1986

Response of colo-rectal hepatic metastases to concomitant radiotherapy and intravenous infusion 5 fluorouracil.

Twenty-three patients with colo-rectal hepatic metastases were retrospectively reviewed after completing treatment with split course liver irradiation and continually infused concomitant intravenous 5-fluorouracil. Although no patient attained a complete response, an objective partial response was documented in 15 (Responders). The Responders had a median survival of 45 weeks whereas Non-responders had a median survival of 17 weeks. Patients with metastatic disease solely in the liver or those with a Karnofsky performance score (k.p.s) of over sixty, had a median survival of 49 weeks. Patients with multiple organ metastatic involvement had a median survival of 25 weeks and those with a Karnofsky with less than 60 had a median survival of 27 weeks. (p values of 0.006 and 0.03, respectively.) The overall survival of the group completing treatment was 30 weeks, and 19 patients (83%) achieved subjective palliation. The patients tolerated therapy well. There was minimal hematological toxicity; 3 patients developed a leucocyte count of less than 2000 and 1 developed a platelet count of 30,000. The palliation and prolongation of survival attained with minimal complications suggest that adjuvant liver irradiation with concomitant infusion 5-fluorouracil radiosensitization may be an option to offer patients identified to be at high risk of developing subclinical liver disease.

Adult↗
PubMed1988

Concomitant 5-fluorouracil, mitomycin-C, and radiotherapy for advanced gynecologic malignancies.

Advanced gynecologic neoplasms continue to pose major therapeutic problems; 22,500 deaths were estimated for 1987. Between December 1983 and October 1985, there were 25 patients evaluated at our institution who on joint evaluation by the radiation oncologist and gynecologic oncologists were found to have extensive disease not amenable to standard therapy. Patients were to be treated by a combined modality approach with Mitomycin-C and 5-Fluorouracil given concomitantly with radiotherapy. Nineteen patients were treated definitively and six patients were treated with palliative intent (24 primary, 1 recurrent). The patients ranged in age from 27 to 90 years with a mean of 57.3 and a median of 57. Primary sites at presentation were: cervix--14 patients, vagina--7 patients, and vulva--4 patients. The initial FIGO stages at time of the initial diagnosis were: Stage I--1 (recurrent), Stage II--4, Stage III--15, and Stage IV--5. Chemotherapy consisted of 5-fluorouracil 1 gm/m2 given continuous infusion for 4 days with Mitomycin-C 10 mg/m2 IV push on day 1. Radiation therapy was started on day 1. Only 2 of 25 patients (8%) required chemotherapy reductions. All 25 patients received mega-voltage irradiation. The external beam dose range was 2000-6500 cGy and 14/25 patients received intracavitary or interstitial therapy. In the definitive patient group, there was no reduction in the therapeutic dose. Only four patients underwent surgical therapy. With a minimum follow-up of 8 months and a median follow-up of 28 months, the survival for the entire population was 56%. Fourteen of the 19 patients (74%) treated definitively are surviving with 12 patients having no evidence of disease. Survival by site in the definitive therapy group was cervix--70%, vulva--100%, and vagina--66%. The overall response rate was 84% at 3 and 9 months (3 months; CR--36%, PR--48%, and 9 months; CR--60%, PR--24%). There were no local recurrences in the 12 patients who achieved a complete response. Three patients died of metastatic disease alone and the overall local control was 60%. Evaluation of therapeutic side effects was performed. Hematologic analysis by the Southeastern Oncology Group criteria showed neutropenia in 14 patients (1--life-threatening, 2--severe, and 11 patients--mild/moderate) and thrombocytopenia was observed in 11 patients (all mild or moderate). All hematologic complications resolved. Acute complications did not appear increased except for the addition of mild oral mucositis (12 patients). Six patients demonstrated late effects with only 2 patients felt to have severe complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

Concomitant 5-fluorouracil infusion, mitomycin C and radical radiation therapy in esophageal squamous cell carcinoma.

This is a retrospective comparison of patients with unresected esophageal squamous cell carcinoma treated by radiation therapy and chemotherapy (21 patients) versus radiation therapy alone (34 patients). Pretreatment characteristics were comparable in both groups. In the combined modality group, treatment was given in split courses with concomitant radiation therapy (20 to 25 Gy in 10 fractions on days 1-12 and days 42-54) and chemotherapy (bolus Mitomycin C on day 1; 96 hr. of continuous 5 Fluorouracil infusion on days 1-4 and days 42-46). There was improvement in local disease control with the combined modality approach. Initial complete response was achieved in 86% of the radiation and chemotherapy group, versus 57% of the radiation alone group. The one-year local relapse-free rate was 67% versus 35%, and 2 year rate was 41% versus 28%. (p less than 0.05). The 1-year and 2-year survival was 64% and 32% respectively, for the radiation and chemotherapy group, versus 28% and 10% respectively for the radiation alone group (p less than 0.05). The majority of patients had disease relapsed, 81% of the combined modality group and 97% of the radiation alone group. However, the pattern of failure was different in the two groups. In the radiation and chemotherapy group, 29% had local failure alone, 53% had distant failure alone, and 18% had both local and distant failure. In the radiation alone group, 33% had local failure alone, 24% had distant failure alone, and 43% had both local and distant failure. Concomitant radiation therapy, 5 Fluorouracil infusion and bolus Mitomycin C is effective treatment for local control in esophageal squamous cell carcinoma, but not for distant hematogenous metastases. This combined modality treatment was well tolerated, with little additional hematological toxicity, esophagitis and stomatitis over radiation therapy alone.

Aged↗
PubMed1992

Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea, and reirradiation.

Head and neck cancer locally recurrent after previous irradiation and surgery presents a difficult management problem. Conventional treatment alternatives include chemotherapy, reirradiation with interstitial implant, and hyperthermia. Reirradiation with external beam is generally not considered because of previous high radiation dose and limited tissue tolerance. In this study, 21 patients with recurrent and previously irradiated head and neck cancer were treated in a Phase I-II fashion. Patients received 5 days of 5-fluorouracil, 300 mg/m2/day IV bolus, Hydroxyurea 1.5 or 2 g/day by mouth and external beam radiation therapy every 2 weeks for up to four courses. Of 20 evaluable patients, 9 have attained a complete response (CR) and 6 a partial response (PR). Fifteen patients completed all planned therapy, eight on time, seven patients with delays. With a median follow-up of 7 months, 13 patients are alive, 7 disease-free (3 after salvage surgery) and 6 with recurrence. Eight patients have died. The 1-year survival is 56%. Treatment toxicity was mainly neutropenia. No major early or late radiation related side effects have been observed at a median follow-up of 7 months. Neither previous radiation dose, time since first radiation, prior chemotherapy, or site of recurrence was predictive of response or treatment tolerance. Patients with a performance status of at least 80 had a significant higher CR rate, with 7/10 patients in this group, as compared to 2/10 patients in patients with a performance status less than 80, achieving a CR. Reirradiation with 5-fluorouracil and hydroxyurea is a well tolerated outpatient treatment program for patients with recurrent and previous irradiated head and neck cancer that produces a high response rate and can provide significant palliation of symptoms.

Adult↗
PubMed1993

Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation +/- 5 fluorouracil.

PURPOSE: Analyze patterns of failure, survival, and tolerance in patients with totally resected ductal adenocarcinoma of the pancreas treated with adjuvant irradiation alone or combined with chemotherapy. METHODS AND MATERIALS: The records of 29 patients treated with radiotherapy following curative resection of pancreas cancer at the Mayo Clinic were retrospectively reviewed. Twenty-two (76%) patients underwent a subtotal pancreatectomy (Whipple procedure), six (21%) a total pancreatectomy, and one (3.5%) a distal pancreatectomy. Twenty-six (90%) had lesions located in the head of the pancreas and three (10%) were located either in the body or tail. Twelve (41%) of the tumors were histologic Grade 3, 15 (52%) Grade 2, and two Grade 1. Contiguous invasion of adjacent tissues or organs was found in fifteen patients (52%) and seventeen (59%) had lymph node involvement. Greater than 75% of patients received more than 45 Gy, with a median dose of 54 Gy, and twenty-seven (93%) patients received concomitant 5-fluorouracil chemotherapy. RESULTS: The median survival was 22.8 months and the 2-year survival 48%. When survival was compared with that achieved with surgery alone in our institution, data suggested a doubling in both median and long-term survival with the addition of adjuvant treatment. Eighty-three percent of patients experienced tumor relapse with seventeen of 29 (59%) developing either liver metastases or peritoneal spread. In three patients, tumors recurred locally; one of one with microscopic residual disease after resection and two of 28 (7%) with negative margins (one of the two was treated with inadequate radiation portals). Patients tolerated adjuvant treatment with minimal acute toxicity consisting mostly of vomiting or nausea which, were controlled with medication in all patients. Chronic toxicity was acceptable; while 5 of 29 (17%) developed some form of possible treatment related complication, only one patient (3.5%) developed a small bowel obstruction. CONCLUSION: These results corroborate data in previous studies which have shown a survival benefit when adjuvant irradiation plus 5-fluorouracil is used in patients with completely resected ductal adenocarcinoma of the pancreas. The patterns of failure indicate that post-operative adjuvant treatment can effectively control disease locally but that future survival improvements will be achieved only by reducing the incidence of liver and peritoneal metastases.

Adult↗
PubMed1995

5-Fluorouracil-radiation interactions in human colon adenocarcinoma cells.

PURPOSE: To determine the effect of cellular proliferation and cell cycle stage on the ability of postirradiation 5-fluorouracil (5-FU) to radiosensitize cultured human colon adenocarcinoma Clone A cells. METHODS AND MATERIALS: Cell survival curves were generated for irradiated: (a) log- and plateau-phase Clone A cells; and (b) Clone A cells separated by centrifugal elutriation into the various phases of the cell cycle; with and without postirradiation treatment with 100 micrograms/ml 5-FU. RESULTS: Postirradiation treatment with 5-FU sensitized proliferating cells to a greater degree than it sensitized cells growing in plateau phase. The beta component of cell kill in log-phase cells was increased by a factor of 1.5 with a sensitizer enhancement ratio of 1.21 at the 0.01 survival level. Plateau-phase cells showed less radiosensitization (sensitizer enhancement ratio of 1.13 at the 0.01 survival level); however, there was a mild increase in both alpha and beta kill in plateau-phase cells. Elutriated G1 cells were the most radiosensitive, independent of treatment with 5-FU. The phase of the cell cycle had little effect on the ability of fluorouracil to radiosensitize Clone A cells. CONCLUSION: Proliferating cells are more susceptible to radiosensitization with 5-FU than plateau-phase cells are, but this effect appears to be independent of the phase of the cell cycle.

Adenocarcinoma↗
PubMed1996

A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.

PURPOSE: To evaluate the toxicities of a Phase I study of radiation therapy with concurrent 5-fluorouracil (5FU) and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. METHODS AND MATERIALS: Twenty-seven patients with locally advanced carcinoma of the pancreas (n = 19), bile duct (n = 7), and gall bladder (n = 1) were entered into a Phase I study of combined radiation therapy, 5FU, and folinic acid. Radiation was given as a split course of 40 Gy in 20 daily fractions with a gap of 2 weeks after 20 Gy. 5-Fluorouracil, 300 to 375 mg/m2/day and folinic acid, 20 mg/m2/day were given as an i.v. bolus daily for 5 days beginning on day 1 and again on day 29. RESULTS: Eight patients developed Grade 3 or 4 toxicities (National Cancer Institute common toxicity criteria) including nausea and vomiting (n = 4), oral mucositis (n = 4), myelosuppression (n = 2), infection (n = 2), and diarrhea (n = 1). Four patients did not complete the planned protocol due to treatment toxicities. There were two treatment deaths secondary to septic neutropenia. Treatment toxicity appeared to be related to age (> 70), performance status (ECOG = 2), and 5FU dose (> 350 mg/m2/day). CONCLUSION: This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol.

Adult↗