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At least 1,009 records · Page 56Linked to original sources
PubMed1985

Role of methotrexate polyglutamates in methotrexate- and sequential methotrexate-5-fluorouracil-mediated cell kill.

The synthesis of methotrexate (MTX) polyglutamates has been investigated in a human leukemia cell line, CCRF-CEM. An increase in either the extracellular MTX concentration (0.1-10 microM) or exposure time (4-24 h) allowed a greater accumulation of polyglutamate derivatives. The species which predominated (di-, tri-, or tetraglutamate) was also time and concentration dependent. Derivatives up to the pentaglutamate were readily detectable, with hexaglutamate present under some conditions. Polyglutamate derivatives were preferentially retained when the cells were transferred to drug-free medium. MTX itself rapidly exited the cells under these conditions. In the absence of extracellular MTX, the performed intracellular MTX polyglutamates continued to be elongated. Accumulation of MTX polyglutamates, particularly triglutamate and longer species, positively correlated with cytotoxicity to CCRF-CEM cells as measured by a clonogenic assay. Investigation of the methotrexate-fluorouracil interaction revealed no effect of 5-fluorouracil on MTX polyglutamate accumulation under various conditions where widely different degrees of cytotoxicity were found. The synergy observed when MTX precedes fluorouracil treatment is therefore not an effect on MTX polyglutamylation. MTX polyglutamates may, however, play an indirect role in this synergy.

Cell Survival↗
PubMed1987

Effect of intracellular folate concentration on the modulation of 5-fluorouracil cytotoxicity by the elevation of phosphoribosylpyrophosphate in cultured human KB cells.

The effects of extracellular folate concentration on intracellular folate and phosphoribosylpyrophosphate (PRPP) levels and the cytotoxicity of methotrexate and 5-fluorouracil were studied in human KB cells grown in fetal bovine serum-supplemented Eagle's minimum essential medium, which contained standard high folic acid levels (2.3 microM) (standard or S medium), or folic acid-free serum-supplemented medium containing approximately 4 nM 5-methyltetrahydrofolate (physiological or P medium), a folate level and form more comparable to that in normal human serum. Macrocytosis and prolongation of the doubling time by 150% were observed after 5-10 serial passes in P medium, but after 10-15 serial passes, KB cells became "adapted" to P medium with return of size and doubling time to values indistinguishable from cells maintained in S medium. Cellular folate levels fell, and marked elevations in PRPP levels from 68 +/- 43 to 642 +/- 287 pmol/mg cell protein (mean +/- SD) were observed as KB cells were serially passed through P medium. Human leukemia HL-60 and K562 cells and MJY-alpha mouse mammary tumor cells serially passed in P medium also exhibited 10- to 20-fold elevations in PRPP levels. Glucose consumption, glucose decarboxylation, thymidine and adenosine specific uptake, thymidine incorporation into DNA, and 5-fluorouracil uptake were studied in KB cells with elevated and control PRPP levels. As determined by clonal assay, despite elevated PRPP levels, KB cells cultured in P medium were less sensitive to 5-fluorouracil than cells cultured in S medium unless exogenous folate was added. These data support the concept that endogenous folate levels may be inadequate for optimal 5-FU pharmacological action in KB cells with a modulated increase in PRPP levels.

Adenosine↗
PubMed1989

Treatment of perimacular proliferations in diabetic ophthalmopathy with fluorouracil.

Five eyes from 4 diabetic patients with proliferations perimacularly were treated with fluorouracil after previous unsuccessful treatment with laser therapy. Fluorouracil was administered in two series of five injections each, every second day in daily doses of 10 to 15 mg subconjunctivally. Fluorouracil was well tolerated. It has a certain inhibitory effect (both on vessels and particularly on the formation of the accompanying fibers) on proliferations reaching the macula at a distance from the vessels out of reach of the visual disc, it has no suppressing effect on papilloretinal proliferations.

Diabetic Retinopathy↗
PubMed1989

Local chemotherapy for rectal polyposis: intraluminal administration of 5-fluorouracil for postoperative control of adenomas in the retained rectum in familial polyposis.

We administered the anticancer drug 5-fluorouracil locally to treat rectal adenomas in four patients with familial adenomatous polyposis who had undergone total colectomy and ileorectal anastomosis. The drug was administered either in suppository form or in high concentration as a rectal enema. One patient was treated successfully with 5-fluorouracil suppositories without any side effects, but the suppository regimen had to be stopped in three other patients because of severe rectal urgency. However, one of these patients was treated effectively with rectal administration of a high-dose 5-fluorouracil solution. Adenomas near the anastomotic site or dentate line were difficult to treat. Although severe urgency was seen in most patients, we think that the intraluminal administration of anticancer agents may prove effective in treating polyposis of the rectum retained after colectomy in familial polyposis. It deserves further study.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Bactericidal and cytotoxic effect of combination of norfloxacin and 5-fluorouracil.

Using the agar dilution technique, we examined the in vitro antibacterial activity of 5-fluorouracil and norfloxacin alone and in association against several bacterial strains. When administered in association, the two drugs did not antagonize each other in tests carried out on strains both sensitive and resistant to penicillins, cephalosporins, aminoglycosides, tetracyclines; furthermore their respective antibacterial properties remained largely unimpaired. The cytotoxic activity and the antitumoral effect of a combination of 5-fluorouracil and norfloxacin was determined in cultured tumor cells, and in mice bearing Ehrlich ascites carcinoma. No significant interference with the cytotoxic activity and antitumoral activity of 5-fluorouracil was observed.

Animals↗
PubMed1989

Low-dose 5-fluorouracil and glaucoma filtration surgery.

We show that a 40-mg total dose of subconjunctival 5-fluorouracil after glaucoma filtering surgery can provide a success rate comparable to that demonstrated in prior studies employing a higher dose. Sixty-four eyes with poor prognoses underwent filtering surgery with postoperative subconjunctival injections of 5 mg of 5-fluorouracil daily for seven days followed by one injection 1 week later. In 75% percent of the eyes intraocular pressure stabilized at 21 mm Hg or less regardless of medications used. The majority of failures occurred within 6 months of treatment. Postoperative corneal epithelial defects occurred in 30% of the cases, conjunctival wound leaks in 6.3%. A 40-mg dose of subconjunctival 5-fluorouracil appears to be effective and may be associated with a lower incidence of postoperative complications than higher doses.

Adolescent↗
PubMed1989

[Adjuvant 5-fluorouracil lacquer administration for reducing the rate of recurrence of condylomata acuminata following laser surgery treatment].

In the recent past we have observed HPV-induced condylomata acuminata with increasing frequency. Providing 60-80% complete remission the laser coagulation is primary in the treatment of condylomata acuminata. However, the generalized mucosal infection with subclinical condylomata acuminata leads to a recurrence in 30-70% of cases. Therefore, we combined laser treatment with adjuvant 5-fluorouracil painting. In a prospective study, 137 patients with a total of 225 treatments were randomly allocated to three groups (laser/laser + 5-FU ointment 5%/Laser + 5-FU 2% painting). After laser treatment only, relapse occurred in 29% of cases, after laser treatment plus 5-fluorouracil 5% ointment in 32%, and after laser treatment and adjuvant 5-fluorouracil 2% painting in only 4%. A topical prophylactic treatment is beneficial because of the multifocal action of HPV. The adjuvant 5-FU painting after laser surgery has been shown to be superior to other treatment modalities with a recurrence rate of only 4%.

Adult↗
PubMed1986

[Cardiotoxicity of 5-fluorouracil. Characteristics, mechanism, practical management].

5-fluorouracil is a drug that is widely used in cancerology. Its cardiotoxicity must be known, as it is not exceptional and potentially dangerous. Two cases are reported in which the coronary insufficiency was documented and recurred when 5-fluorouracil was reintroduced. The mechanism of cardiac toxicity seems to be coronary spasm, as shown by exercise tests and the normal results of coronary arteriography. It seems preferable to refrain from using 5-fluorouracil after a recent myocardial infarction or in patients with unstable angina. Reintroduction of the drug is usually followed by recurrence of cardiotoxicity, even under coronary vasodilators.

Coronary Disease↗
PubMed1988

Leucovorin and 5-fluorouracil as a treatment for disseminated cancer of the pancreas and unknown primary tumors.

Chemotherapy with leucovorin (100 to 200 mg) and 5-fluorouracil (30 mg/kg) every 2 wk produced four (three complete) objective responses among a group of eight patients with early metastatic pancreatic primary and unknown cancers. Complete remissions were associated with exceptionally long durations of survival, one in a patient failing prior combination chemotherapy. This treatment warrants testing because of its ease, scientific rationale, and the large population of patients with early metastatic pancreatic cancer for whom there is no accepted treatment. Early metastatic disease is defined as small metastatic lesions not immediately life threatening found in a physiologically intact patient. Controlled trials, demonstrating benefit associated with other 5-fluorouracil-containing regimens for patients with nonmetastatic stages of pancreatic cancer, provide a rationale for extending testing of leucovorin and 5-fluorouracil to other early stages of pancreatic cancer.

Adult↗
PubMed1978

Altered toxicity of 5-fluorouracil following treatment with Corynebacterium parvum.

Recent studies have demonstrated that systemic Corynebacterium parvum increases serum granulocyte-macrophage colony-stimulating factor and stimulates the proliferation of granulocyte-macrophage progenitor cells. It was hypothesized that more rapid cycling of granulocyte-macrophage progenitor cells would render the cells more sensitive to a cell cycle-specific chemotherapeutic agent. The colony-forming ability of bone marrow granulocyte-macrophage progenitor cells was assayed in vitro with soft agar cultures. C. parvum given before 5-fluorouracil in C57BL/6 mice increased the granulocyte-macrophage progenitor cell toxicity, the lymphopenic effect, and the lethality of 5-fluorouracil. When C. parvum was given after 5-fluorouracil, there was more rapid rebound of granulocyte counts to normal or supranormal levels.

Animals↗
PubMed1988

[Current studies of sequential methotrexate and 5-fluorouracil treatment in cancer chemotherapy].

This paper reviews the data on the clinical studies of sequential methotrexate and 5-fluorouracil in advanced colorectal, gastric, head and neck, and breast cancer. To date, a lot of phase II studies have been conducted, but there are many distance in each clinical data concerning response rate and side effect by the difference between their clinical methods with respect to the interval between methotrexate and 5-fluorouracil, or the dosage of each drugs. There are several reports with high response rate in those phase II studies, but randomized controlled studies recently reported have not yet confirmed the sequential effect of MTX-5-FU treatment. Therefore, it is concluded that the randomized controlled studies with the most available methods must be performed to evaluate the true efficacy of sequential methotrexate and 5-fluorouracil treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1978

Disposition and metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) in humans.

The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 microgram/ml) for at least 48 hr after FT administration. The concentrations of FUra derived from the administration of FT were considerably greater than were those achieved by constant infusion of FUra at the maximal tolerated dose of 1.1 g/sq m without causing unacceptable mucositis. The cumulative urinary excretion was 20% of the administered dose in 24 hr. FT underwent in vivo biotransformation to 2 hydroxytetrahydrofuranyl-5-fluorouracil derivatives in addition to anabolites and catabolites of FUra. High concentrations of FT and FUra were present in the cerebrospinal fluid, which could account for the severe central nervous system toxicity of FT at high doses. We conclude that the antitumor activity of FT is partially attributable to its slow release of FUra.

Animals↗
PubMed1987

Structural and dynamic properties of a fluorouracil-adenine base pair in DNA studied by proton NMR.

An oligodeoxynucleotide duplex containing the chemotherapeutic agent 5-fluorouracil (FU) has been constructed by solid phase phosphotriester synthesis and has been studied in solution by proton NMR. In this study, we provide the first structural characterization of a DNA complex containing a FU.A base pair. It has been determined that the 7-mer duplex containing a central FU.A base pair adopts a normal right-handed configuration and the A residue in the FU.A pair is oriented in the normal anticonfiguration giving a Watson-Crick base pair. The significant difference between T.A and FU.A base pairs is dynamic, not structural: the FU.A base pair opens faster than normal base pairs in the oligonucleotide studied. We provide evidence that the FU.A base pair has a significantly enhanced opening rate resulting form decreased stacking of the 5-fluorouracil residue and not from the enhanced acidity of the 5'-fluorouracil imino proton.

Adenine↗
PubMed1987

Synthesis and antitumor activity of 1- or 3-(alpha-hetero substituted)alkyl-5-fluorouracil derivatives.

Two classes of 5-fluorouracil (5-FU) derivatives were prepared from 1,3-bis(hydroxymethyl)-5-fluorouracil (1). The first group was obtained by the direct esterification of 1 with various acids. The second one was derived by the nucleophilic substitution of N-(chloromethyl)-5-FUs, which were easily prepared by halogenation of 1, with hetero nucleophiles. The antitumor activities of the prepared compounds were examined against Leukemia L1210 and the results were compared with that of 1-hexylcarbamoyl-5-fluorouracil (HCFU, Carmofur).

Animals↗
PubMed1986

[A randomized controlled study of (2'' R)-4'-O-tetrahydropyranyladriamycin and adriamycin in combination with cyclophosphamide and 5-fluorouracil in the treatment of advanced and recurrent breast cancer].

A comparative study of two combination chemotherapy regimens including (2'' R)-4'-O-Tetrahydropyranyladriamycin (THP) or Adriamycin (ADR) was performed to evaluate its efficacy and safety in advanced and recurrent breast cancer. In this study 64 patients were evaluated, and the response rate was 35.1% (13 of 37 patients) in group A (combination chemotherapy of THP, 5-Fluorouracil and cyclophosphamide), and 29.6% (8 of 27 patients) in group B (ADR, 5-Fluorouracil and cyclophosphamide). There was no statistically significant difference between the response rates of the two groups. As for safety, that of group A was significantly superior to group B for alopecia while that of group A tended to be lower than group B for anorexia. From the above results, THP in combination with cyclophosphamide and 5-Fluorouracil is comparable to ADR in efficacy and can be regarded as having better safety than ADR for the treatment of breast cancer.

Anorexia↗
PubMed1986

[Use of the polyamine test in the joint administration of 5-fluorouracil and indomethacin in stomach cancer patients].

Excretion of polyamines (spermine, spermidine and putrescine) with the urine was studied in patients with carcinoma of the stomach of the III-IV stage after intravenous injection of 5-fluorouracil and indomethacin. A 40% increase of the polyamine level in the urine was observed at the beginning and towards the end of drug infusion course as well as a decrease of these indices at the top point of chemotherapy and towards the end of it. It is emphasized that an increase of the polyamine amount following the separate use of 5-fluorouracil is less expressed than following combined use of 5-fluorouracil and indomethacin.

Adult↗
PubMed1979

Human urinary metabolites of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftoraful).

Two hydroxylated metabolites were isolated from the urine of a patient who had received ftorafur (5 g/sq m). These metabolites were identified by mass spectrometry and nuclear magnetic resonance spectroscopy as trans-3'- and cis-4'-hydroxyftorafur. The compounds were not converted to 4-fluorouracil when incubated in plasma, base (pH 9), or water. Because of their stability, it is unlikely that these metabolites are in vivo precursors of 5-fluorouracil. There are indications that less stable, unisolatable, hydroxylated ftorafur derivatives are intermediates in the conversion of ftorafur to 5-fluorouracil.

Chemical Phenomena↗
PubMed1986

5-Fluorouracil treatment of a human colon adenocarcinoma implanted in the subrenal capsule site of athymic mice.

5-Fluorouracil was used in the treatment of a recently established. human adenocolon carcinoma implanted in the subrenal capsule site of athymic mice as part of a program to determine the relative effectiveness of antitumor agents in the treatment of human tumors grown as xenografts and in the clinic. 5-Fluorouracil treatments resulted in a dose-dependent inhibition of tumor growth under the two examined schedules (five daily doses and three doses every 4 days) when administered either i.v. or i.p. The various schedules and routes resulted in similar patterns of antitumor effects when the data were based on the endpoints of either final tumor weight, change in tumor weight, or relative tumor weight. Assessments of cell viability based on histological examination of tumored kidneys resulted in a downward displacement of the dose-response curves but did not alter their shape or the interpretation of the data. Although approximately 1-mm3 tumor fragments were implanted, variability of size was allowed. Tumor growth was not dependent on the initial size of the implant, as shown by a comparison between the initial individual or average tumor sizes and the final individual or average tumor sizes, respectively. The antitumor effects of the 5-fluorouracil could have been determined on the basis of final tumor weight alone. The inhibition of tumor growth was accompanied by weight loss in treated mice as compared with controls. At lower doses, however, the weight loss of the mice was not extensive, which indicated that the inhibition of tumor growth was, at least in part, attributable to some selective antitumor action of the 5-FUra. The greatest inhibition of tumor growth, however, was accompanied by the most extensive animal weight loss. This correlation raised the question of the degree to which the tumor growth inhibition observed was a consequence of nonspecific drug toxicity to the host. The current results stress the importance of detailed investigations into the nature of host-tumor parameters in order to assess the antitumor activity of candidate drugs in the treatment of human tumor xenografts.

Adenocarcinoma↗