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PubMed1985

Allopurinol mouthwashes and 5-fluorouracil induced oral toxicity.

Allopurinol has been shown to decrease the gastro-intestinal and bone marrow toxicity of 5-fluorouracil. In an attempt to diminish mucositis resulting from 5-fluorouracil administration, whilst not affecting its systemic anti-tumour activity, an allopurinol mouthwash has been used. In six patients who experienced mucositis when treated initially with 5-fluorouracil, the use of an allopurinol mouthwash with subsequent courses resulted in a reduction of oral toxicity.

Allopurinol↗

PubMed1979

Determination of 5-fluorouracil in plasma by GC/MS using an internal standard. Applications to pharmacokinetics.

An analytic method, sensitive to 5 ng/ml and specific, has been set up for the determination of unchanged 5-fluorouracil in human plasma, using gas chromatography--mass spectrometry. Its applications to the pharmacokinetic study of unchanged 5-Fluorouracil in man following an intravenous bolus, 8 hours infusion and oral administration confirmed the non-linearity of the kinetic model. (The clearances obtained with an infusion--from 5 to 60 1/min--are 10 to 60 times higher than the ones observed with a bolus--from 0.5 to 1.4 1/min.) The bioavailability of the oral form seems to be about 60 per cent and the absorption appears to be very fast. A attempt to search a mathematical non-linear model of the 5-Fluorouracil kinetics, using computer simulation, is presented.

Administration, Oral↗

PubMed1981

The effect of 5-fluorouracil and 5-fluorocytosine on the development of the filarial nematodes Brugia pahangi and Dirofilaria immitis.

5-fluorouracil and 5-fluorodeoxyuridine at 30 mg/kg body weight daily for four days inhibit microfilarial production in Brugia pahangi in the jird. Disruption of intrauterine embryogenesis was observed in treated female worms but the compounds were not macrofilaricidal or microfilaricidal under the conditions employed. 5-fluorocytosine possessed no filaricidal or embryostatic activity. The inhibition of microfilaria production by 5-fluorouracil was temporary and larval production was resumed within nine weeks. The compound also inhibited the development of B. pahangi and Dirofilaria immitis larvae in the mosquito Aedes aegypti, when administered to cages of mosquitoes as a 0.01 or 0.001% solution in a 10% aqueous sucrose solution on cotton wool wicks. The development of infective larvae of B. pahangi in the jird was inhibited by 5-fluorouracil.

Animals↗

PubMed1980

[Effect of 5-fluorouracil on the enzymatic activity of the pancreas and blood serum of rats with acute pancreatitis].

The effect of 5-fluorouracil on the activity of pancreatic enzymes was studied in rats with acute pancreatitis. 5-Fluorouracil was injected intraperitoneally in a dose of 4.5 mg per 100 g body weight. Pancreatic transaminidase as well as serum alpha-amylase and trypsin levels decreased starting from 3--6h after the induction of acute pancreatitis. 5-Fluorouracil inhibited RNA and DNA synthesis and blocked the synthesis of pancreatic enzymes.

Acute Disease↗

PubMed1977

Combination chemotherapy for solid tumors using 5-fluorouracil, chromomycin-A, and prednisolone.

Clinical effect of 5-fluorouracil or chromomycin-A3 alone, 5-fluorouracil + chromomycin-A3, and of the first two plus prednisolone on gastrointestinal and other solid tumors was evaluated. Out of 133 cases acceptable for evaluation, the number of responders was as follows: 3 (18.8%) of 6 cases treated with 5-fluorouracil alone, 1 (9.1%) of 11 cases treated with chromomycin-A3 or chromomycin-A3 hemisuccinate, 13 (21.7%) of 60 cases on the two-drug regimen, and 21 (45.7%) of 46 cases on the three-drug regimen. In cases of stomach carcinoma, response rate to the three-drug regimen was 54.2% (13/24), significantly higher than that of other regimens. At least 25% regression in the size of primary tumor was observed in 2 (7.1%) of 28 cases on the two-drug regimen and in 6 (33.3%) of 18 cases on the three-drug regimen. Of 51 cases on the three-drug regimen, steroid diabetes developed in 5 cases, moon face in 4 cases, and gastric ulcer in 1 case. However, toxic effect of these regimens (especially appearance of leucopenia) was less than those of previously tried combined regimens. The duration of response, on an average, was 10.8 weeks in 13 cases on the two-drug regimen and 11.7 weeks in 21 cases on the three-drug regimen. It was concluded from these results that a better response is obtained by the three-drug regimen than other regimens, and that prednisolone in combination, in addition to its favorable effect in improving the general condition of the patients, might enhance the anticancer effect of the drugs used in combination.

Adenocarcinoma↗

PubMed1984

Mitoxantrone, cyclophosphamide, and 5-fluorouracil in the treatment of hormonally unresponsive metastatic breast cancer.

Fifty-five patients with newly diagnosed, estrogen receptor negative, metastatic breast cancer were entered in a trial of mitoxantrone, 10 mg/m2 intravenous (IV), cyclophosphamide, 500 mg/m2 IV, and 5-fluorouracil, 1000 mg/m2 IV, which were given on day 1 of a 21-day treatment interval. This trial was designed to test the efficacy of substituting mitoxantrone for doxorubicin as part of a combination that has proved to be effective in inducing remission. The trial was also intended to evaluate the response of resistant disease and of stable metastatic disease to a combination of doxorubicin and vinblastine sulfate. The cardiotoxic potential of mitoxantrone was evaluated in all the patients by serial measurements of ejection fraction and by endocardial biopsy of the right ventricle. Patients who achieved a complete response or a partial response (with bone as the only site of disease) on the three-drug combination were continued on this treatment for 2 years, or for 1 year following a complete response, whichever was shorter or as cardiac monitoring permitted. Therapy with doxorubicin, 25 mg/m2/d for two days, followed by continuous infusion vinblastine sulfate, 1.4 mg/m2/d for four days, was given to all patients who progressed after two courses or were stable after six courses of three-drug therapy. The preliminary results from 50 patients show that 4 attained a complete response and 30 a partial response, giving a total response rate of 68%. The median duration of response was more than 7 months (range greater than 5 to greater than 15 months). One patient in complete remission relapsed after 8 months and failed reinduction therapy with doxorubicin-vinblastine sulfate. Myelosuppression, principally granulocytopenia, was the major side effect of cyclophosphamide-mitoxantrone-5-fluorouracil. Mild to moderate vomiting occurred in 76% of patients and alopecia in 88%. This therapy was discontinued in four patients because of a decreased cardiac ejection fraction and/or symptoms of heart failure. No cardiac biopsy score, however, has been greater than 1.0. These results suggest that a combination of cyclophosphamide-mitoxantrone-5-fluorouracil is effective in untreated, estrogen receptor negative, metastatic breast cancer and is comparable to the doxorubicin combination. Myocardial injury occurs with mitoxantrone, and a safe cumulative dose has yet to be established.

Adult↗

PubMed1984

Effects of vinblastine and 5-fluorouracil on human glioma and thyroid cancer cell monolayers and spheroids.

The effects of the two antitumor drugs vinblastine and 5-fluorouracil on the growth of the human tumor cell lines U-118 MG (glioma) and HTh-7 (thyroid cancer) were analyzed. The cells were cultured both as monolayers and as multicellular spheroids and exposed to vinblastine (0.1, 1.0, or 10 micrograms/ml) or 5-fluorouracil (10, 100, or 1000 micrograms/ml) for 15 min, 2 hr, or 24 hr. The drugs induced growth delays of the monolayers and delays in the outgrowth of cells from spheroids which were placed on cell-adhesive surfaces. Cell cultures exposed to sublethal drug doses showed a dose-dependent lag period followed by regrowth at normal growth rates. In all cases with vinblastine exposures, the spheroids seemed more resistant to the drug treatments than did the monolayer cultures. Much smaller differences were obtained after treatments with 5-fluorouracil. The three-dimensional arrangement of cells in spheroids giving rise to, e.g., nutrient and proliferation gradients may, to some extent, be responsible for the increased resistance. The spheroids were especially resistant to short treatments with vinblastine. This was probably due to penetration barriers.

Cell Division↗

PubMed1984

Increased levels of thymidylate synthetase in cells exposed to 5-fluorouracil.

The binding of 5-fluoro-2'-deoxyuridylate, methylenetetrahydrofolate, and thymidylate synthetase in a ternary complex results in enzyme inhibition and is a major component of 5-fluorouracil cytotoxicity in some cells. The amount of 5-fluoro-2'-deoxyuridylate bound to thymidylate synthetase in several human gastrointestinal tumor cell lines following 5-fluorouracil exposure was determined, using Sephadex G-25 chromatography and high-pressure chromatographic analysis. These data were compared with previously determined values for thymidylate synthetase levels in control cultures not exposed to 5-fluorouracil. In HuTu 80 cells, the amount of 5-fluoro-2'-deoxyuridylate bound to thymidylate synthetase represented 16% of the total amount of enzyme present in untreated cells. The values for 5-fluoro-2'-deoxyuridylate bound to thymidylate synthetase in the WIDR and HT 29 cell lines (57 and 46 fmoles/10(5) cells, respectively), however, exceed by 3- to 6-fold the total amount of this enzyme found in untreated cells. The presence of increased levels of thymidylate synthetase protein in these cell lines was confirmed by sodium dodecyl sulfate gel electrophoresis. Measurements of thymidylate synthetase levels following exposure of cells to cycloheximide demonstrated that thymidylate synthetase complexed to 5-fluoro-2'-deoxyuridylate has increased stability as compared with uncomplexed enzyme. The level of thymidylate synthetase (bound and free) present in WIDR cells was measured following removal of FUra from the media. After 48 hr, the level of bound enzyme had fallen from 53 to 14 fmoles/10(5) cells, whereas free enzyme, which was undetectable after a 24-hr exposure to FUra, returned to 60% of its level in untreated cells.

Cell Line↗

PubMed1984

Histidinol-mediated improvement in the specificity of 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil in L 1210 leukemia-bearing mice.

We have demonstrated previously that L-histidinol, a structural analogue of the essential amino acid L-histidine, protects a variety of phenotypically normal cell lines from certain proliferation-dependent anticancer drugs without decreasing the toxicity of these agents for corresponding tumorigenic derivatives of the normal cells. Histidinol modulates the toxicity of selected anticancer drugs in tissue culture systems by its ability to arrest, specifically and reversibly, cells of normal phenotype in a G0-like, noncycling state while allowing continued cell cycle transit in most of their tumorigenic counterparts. Thus, in the presence of comparable levels of histidinol, the toxicities of the proliferation-dependent anticancer drugs 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil are eliminated for a variety of normal cell lines but significantly increased for a number of tumorigenic lines. We report here that histidinol confers substantial protection upon the bone marrow cells of DBA/2J mice from the drugs 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil. The protective responses were evaluated by quantitative cell survival assays and by animal survival studies. We report also that the histidinol-mediated protection to bone marrow cells persists in L1210 leukemia-bearing DBA/2J mice treated with combinations of histidinol and 1-beta-D-arabinofuranosylcytosine or 5-fluorouracil without diminishing the toxicities of these agents for in situ leukemia cells.

Animals↗

PubMed1980

Inhibition of phosphoribosylation of 5-fluorouracil by purines.

The mechanism of the reversal of 5-fluorouracil cytotoxicity in L5178Y cells by hypoxanthine, adenine and inosine was examined in a cell-free system. A crude extract of the cells possessed high hypoxanthine and adenine phosphoribosyltransferase and purine nucleoside phosphorylase activities. Hypoxanthine (2 mM), adenine (5 mM) and inosine (5 mM) inhibited the nucleotide formation from 5-fluorouracil at 0.2 mM 5-phosphoribosyl 1-pyrophosphate (PRPP). However, at a higher concentration of PRPP (2.5 mM), the inhibition of hypoxanthine was not found. It suggests that the inhibition of 5-fluorouracil metabolism is due to a deficiency of PRPP induced by phosphoribosylation of hypoxanthine and adenine.

Adenine↗

PubMed1983

The effect of 5-fluorouracil on DNA synthesis in the rat liver undergoing compensatory hyperplasia after partial hepatectomy.

An investigation has been made into the effects of 5-fluorouracil (5FU) on DNA synthesis after partial hepatectomy. Animals underwent in vivo isolated liver perfusion with 5-fluorouracil followed by partial hepatectomy or Sham hepatectomy. Controls consisted of animals whose liver was perfused with 0.9% saline. Liver weight and DNA synthesis were recorded at various times following 5-fluorouracil perfusion and partial hepatectomy and control procedures. The results have shown that perfusion with large concentrations of the cytotoxic agent (5 FU) can be performed without apparent serious side effects on liver weight and with only minimal delay in liver cell proliferation.

Animals↗

PubMed1983

Sequence-dependent synergism between dichloromethotrexate and 5-fluorouracil in a human colon carcinoma cell line.

Prior to their use in patients with hepatic metastasis of colon cancer, we studied the cell-killing effects of 5-fluorouracil, 5-fluoro-2'-deoxyuridine, 3',5'-dichloromethotrexate (DCM), and 5-fluoro-2'-deoxyuridine, 3',5'-dichloromethotrexate (DCM), and combinations of these fluoropyrimidines with DCM on a human colon carcinoma cell line (HCT-8). Sequential exposure of these cells to DCM followed by 5-fluorouracil resulted in significant synergistic cell killing at every dose and time studied, and the synergy was more evident with increasing doses of both drugs. In contrast, simple additive effects were observed when DCM was given together with or following 5-fluorouracil. When the antifolate was given before 5-fluoro-2'-deoxyuridine, simple additive effects, rather than synergy, were observed. Mild antagonism and even strong antagonism were found when 5-fluoro-2'-deoxyuridine preceded DCM administration or when the cells were exposed to the drugs simultaneously, respectively.

Antineoplastic Agents↗

PubMed1982

Treatment of keratoacanthoma with topical application of fluorouracil.

Keratoacanthomas (KAs) in 14 patients were treated with 20% fluorouracil ointment, two or three times daily, for two to four weeks. All lesions responded promptly and cleared in an average period of 3.4 weeks (range, one to seven weeks). Allergic contact dermatitis to fluorouracil occurred in two patients. This treatment response suggests that topical application of fluorouracil ointment is an effective alternative to conventional methods of treating KA.

Administration, Topical↗

PubMed1980

Cell surface alterations associated with exposure of leukemia L1210 cells to fluorouracil.

Exposure of murine leukemia L1210 cells to graded doses of 5-fluorouracil for 24 hr led to a progressive increase in cell surface hydrophobicity, inhibition of cell division, an an increased cell volume. Among the effects associated with fluorouracil treatment were inhibition of thymidylate synthetase, decreased incorporation of leucine into glycoprotein, and an apparently increased incorporation of thymidine into DNA and of glucosamine into glycoprotein. The latter effects are believed to be caused by depleted metabolite pools. Short-term treatment of L1210 cells with the drug altered only levels of thymidylate synthetase. Cell surface changes therefore appear to be related to long-term effects of fluorouracil associated with impaired synthesis of membrane glycoprotein.

Animals↗

PubMed1980

Effect of microwave radiation on redissolving precipitated matter in fluorouracil injection.

The effect on the stability of fluorouracil injection of using microwave radiation to redissolve precipitated matter was studied. Fifteen ampuls each of Fluorouracil Injection, USP, containing precipitate were heated to 60 degrees C in a microwave oven and water bath, respectively. The contents of each heated ampul and of 15 control ampuls (unheated, no precipitate) were assayed by high-performance liquid chromatography, and the pH value of each sample was measured. Each test group fell within USP concentration requirements and showed no significant decrease in potency. Among the microwave-heated ampuls, a mean drop of 0.03 pH units was significant (p less than 0.05) but did not affect drug stability or solubility, since all samples remained within the USP pH range of 8.6-9.0. Precipitated matter in fluorouracil injection can be redissolved by heating with microwave radiation without significantly affecting the drug's stability.

Chemical Precipitation↗

PubMed1980

Unusual pigmentary changes associated with 5-fluorouracil therapy.

A fifty-six year old black man with stage D carcinoma of the prostate was treated weekly with 5-fluorouracil 750 mg/m2 for twenty-four consecutive doses. The total amount received was 27 gm. A good partial remission was attained. Little hematologic and no gastrointestinal or central nervous system toxicity was experienced. The patient did experience nasal mucosal friability and diffuse hyperpigmentation of the face and hands. Markedly increased pigmementation of skin immediately overlying veins used for multiple 5-fluorouracil infusions was noted. Because of its unusual appearance, the name serpentine supravenous fluorouracil hyperpigmentation is suggested for this entity.

Fluorouracil↗

PubMed1980

Morphological study of cleft palate development in 5-fluorouracil-treated hamster fetuses.

Morphogenesis of palate was studied in normal and 5-fluorouracil-treated hamster fetuses. The results showed that normal palatal development was completed between days 12 and 13 of gestation. In 5-fluorouracil-assaulted palate the reorientation of shelves from a vertical to horizontal plane was delayed. Crown-rump length, gestational age and fetal weight were reliable predictors of the stages of normal palatal development, whereas the morphological rating system was not. Following 5-fluorouracil treatment, however, crown-rump length, weight and morphological rating were poor indicators of the stage of palatal development.

Abnormalities, Drug-Induced↗

PubMed1981

Topical chemotherapy of dysplastic melanocytic nevi with 5% fluorouracil.

A therapeutic response to topical fluorouracil in a patient with the large atypical nevus syndrome is presented. Six of the patients' dysplastic melanocytic nevi were treated with topical fluorouracil. Four common acquired melanocytic nevi from normal individuals were also treated. All six dysplastic nevi responded with inflammation, ulceration, and subsequent disappearance of the lesion, while the four control melanocytic nevi remained unchanged. Although we do not presently advocate the therapeutic use of fluorouracil for large atypical nevi until its safety and efficacy have been established, the response reported herein may herald an important advance in the therapy of these troublesome lesions that are known to be histogenetic precursors of malignant melanoma.

Administration, Topical↗