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At least 145 records · Page 8Linked to original sources
PubMed1998

Nucleosides and nucleotides. 175. Structural requirements of the sugar moiety for the antitumor activities of new nucleoside antimetabolites, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine and -uracil1.

We previously designed 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)uracil (EUrd) and its cytosine congener (ECyd) as potential multifunctional antitumor nucleoside antimetabolites. They showed potent and broad-spectrum antitumor activity against various human and mouse tumor cells in vitro and in vivo. To clarify the structure-activity relationship of the sugar moiety, various 3'-C-carbon-substituted analogues, such as 1-propynyl, 1-butynyl, ethenyl, ethyl, and cyclopropyl derivatives, of ECyd and EUrd were synthesized. We also prepared 3'-deoxy analogues and 3'-homologues of ECyd and EUrd with different configurations to determine the role of the 3'-hydroxyl group and the length between the 3'-carbon atom and the ethynyl group and a 2'-ethynyl derivative of ECyd to determine the spatial requirements of the ethynyl group. The in vitro tumor cell growth inhibitory activities of these nucleosides against mouse leukemic L1210 and human KB cells showed that ECyd and EUrd were the most potent inhibitors in the series, with IC50 values of 0.016 and 0.13 microM for L1210 cells and 0.028 and 0.029 microM for KB cells, respectively. Only 3'-C-1-propynyl and -ethenyl derivatives of ECyd showed greatly reduced cytotoxicity. We found that the cytotoxic activity of these nucleosides predominantly depended on their first phosphorylation by uridine/cytidine kinase.

Animals↗
PubMed1998

Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia.

Etoposide, an effective agent for acute lymphoblastic leukemia (ALL), can cause secondary acute myeloid leukemia (AML) in a subset of patients. Our objectives were to determine whether patients who develop secondary AML displayed altered etoposide pharmacokinetics or other pharmacologic characteristics compared to identically treated patients who did not develop AML. Children with newly diagnosed ALL were treated according to a protocol which included etoposide 300 mg/m2 given three times over 8 days during remission induction and once every 2-4 weeks during 120 weeks of continuation therapy. Characteristic 11q23 rearrangements were documented in seven of the eight patients with AML. Etoposide clearance, time that etoposide concentrations exceeded 10 microM, etoposide or etoposide catechol area-under-the-plasma-concentration vs time curve (AUC), serum albumin, and average methotrexate concentration did not differ significantly between the two groups; thiopurine methyltransferase (TPMT) activity tended to be lower in the eight children who did vs the 23 matched control children who did not develop AML (P=0.16). Further regression analyses likewise indicated that lower TPMT activity tended to be associated with shorter onset of secondary AML (P=0.11); it also tended to be lower among the eight index cases compared to the entire unmatched cohort of 105 identically treated children with ALL (P=0.10). We observed no statistically significant differences in etoposide disposition and antimetabolite pharmacology between patients who did and did not develop secondary AML.

Adolescent↗
PubMed1965

THE INHIBITION OF TWO STEROID-ACTIVATED NICOTINAMIDE-ADENINE DINUCLEOTIDE (PHOSPHATE) TRANSHYDROGENASES BY FOLIC ACID AND FOLIC ACID ANTIMETABOLITES.

1. It was found that steroid-mediated nicotinamide-adenine dinucleotide (phosphate) transhydrogenases can be inhibited in vitro by folic acid and its antimetabolites. The most potent inhibitor was methotrexate, a drug with a high therapeutic index against experimental cancer. 2. The inhibitions produced by a combination of folic acid and the analogues were additive, as were those between the folic acid compounds and antagonistic steroid hormones.

Aminopterin↗
PubMed1992

Assay method for monitoring the inhibitory effects of antimetabolites on the activity of inosinate dehydrogenase in intact human CEM lymphocytes.

A rapid and convenient method has been developed to monitor the inhibition of inosinate (IMP) dehydrogenase by antimetabolites in intact human CEM lymphocytes. This method is based on the determination of 3H release from [2,8-3H]hypoxanthine ([2,8-3H]Hx) or [2,8-3H]inosine ([2,8-3H]Ino). The validity of this procedure was assessed by evaluating IMP dehydrogenase inhibition in intact CEM cells by the well-known IMP dehydrogenase inhibitors ribavirin, mycophenolic acid and tiazofurin. As reference materials, several compounds that are targeted at other enzymes in de novo purine nucleotide anabolism (i.e. hadacidine, acivicin) or catabolism (i.e. 8-aminoguanosine, allopurinol) were evaluated. There was a strong correlation between the inhibitory effects of the IMP dehydrogenase inhibitors (ribavirin, mycophenolic acid, tiazofurin) on 3H release from [2,8-3H]Hx and [2,8-3H]Ino in intact CEM cells and their ability to decrease intracellular GTP pool levels. The other compounds (hadacidine, acivicin, 8-aminoguanosine, allopurinol) had no marked effect on 3H release from [2,8-3H]Hx. Using this method, we demonstrated that the novel ribavirin analogue, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, is a potent inhibitor of IMP dehydrogenase in intact cells.

Adenosine Triphosphate↗
PubMed2003

Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites.

BACKGROUND: Ataxia-telangiectasia is a pleiotropic autosomal recessive disorder caused by mutations in the ATM gene. In addition to a profound cancer predisposition, another hallmark of ataxia-telangiectasia is radiosensitivity. Recently, p53-null mouse fibroblasts have been reported to be radiosensitised by the concurrent loss of ATM. MATERIALS AND METHODS: We compared the sensitivity of atm(+/+)/p53(-/-) and atm(-/-)/p53(-/-) mouse embryonic fibroblasts to different classes of chemotherapeutic agents using the MTT assay, Trypan Blue exclusion and fluorescence-activated cell sorting for cell cycle and apoptosis analyses. RESULTS: Loss of ATM function in p53-deficient cells resulted in a 2- to 4-fold increase in sensitivity to the topoisomerase I poisons camptothecin and topotecan, to the topoisomerase II poisons doxorubicin, epirubicin and etoposide, and to the antimetabolites 5-fluorouracil and gemcitabine, but not to the platinum compounds cisplatin, carboplatin and oxaliplatin, the taxanes docetaxel and paclitaxel, or to busulfan. Loss of ATM function did not result in increased apoptosis, but resulted in increased Trypan Blue staining in response to epirubicin, suggesting that processes other than apoptosis may mediate cytotoxicity. ATM deficiency did not alter the extent of G(1)/S or G(2)/M cell cycle phase accumulation produced by epirubicin, suggesting that enhanced sensitivity was not due to failure of checkpoint activation. CONCLUSIONS: We provide further evidence that ATM is involved in regulating cellular defences against some cytotoxic agents in the absence of p53. Tumour-targeted functional inhibition of ATM may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers.

Animals↗
PubMed1998

Antimetabolites in ocular surface neoplasia.

Malignant neoplasms of the ocular surface are uncommon but consist of squamous and melanocytic tumors. Surgical excision has been the mainstay of treatment and is perhaps the "gold standard." However, in those circumstances in which surgical intervention is not feasible, adjunctive treatments have been advocated. Recent attention has been given to the use of mitomycin C and 5-fluorouracil for the treatment of ocular surface squamous neoplasia. This article reviews the major publications relating to the use of antimetabolites in ocular surface neoplasia and highlights the most recent contributions to the ophthalmic literature.

Antimetabolites, Antineoplastic↗
PubMed1982

Mode of action of the biotin antimetabolites actithiazic acid and alpha-methyldethiobiotin.

Actithiazic acid and alpha-methyldethiobiotin inhibited the conversion of dethiobiotin to biotin resting-cell suspensions of Escherichia coli. The concentrations which effected 50% inhibition were 0.45 and 1.1 microM for actithiazic acid and alpha-methyldethiobiotin, respectively. Cells grown in low concentrations of the two biotin antimetabolites showed derepression of the biotin A operon, as evidenced by the enhanced levels of the enzymes 7,8-diaminopelargonic acid aminotransferase and dethiobiotin synthetase. Derepression was not due to any direct regulatory effect of the antibiotics but was the consequence of the inhibition of the biotin synthetase enzyme; this inhibition prevented the intracellular concentration of biotin from reaching the levels required for normal regulation of the biotin A operon.

Anti-Bacterial Agents↗
PubMed1973

U-42, 126, a new antimetabolite antibiotic: production, biological activity, and taxonomy of the producing microorganism.

A new antimetabolite antibiotic, U-42,126, was discovered by use of a specific in vitro screen. U-42,126 was produced by the fermentation of Streptomyces sviceus. Its antimicrobial activity in vitro was limited to fungi. Certain bacteria were inhibited only when cultivated in completely synthetic media. U-42,126 was active in vivo against L1210 leukemia in mice.

Antibiotics, Antineoplastic↗
PubMed1998

Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study.

PURPOSE: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C). RESULTS: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A. CONCLUSION: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).

Antimetabolites, Antineoplastic↗
PubMed2003

Thioguanine, mercaptopurine: their analogs and nucleosides as antimetabolites.

6-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs of the natural purines: hypoxanthine and guanine. Both mercaptopurine and thioguanine are substrates for hypoxanthine-guanine phosphoribosyltransferase and are converted into the ribonucleotides 6-thioguanosine monophosphate (6-thioGMP) and 6-thioinosine monophosphate (T-IMP) respectively. The accumulation of these monophosphates inhibits several vital metabolic reactions. Today, these thiopurine bases remain valuable agents for the induction and maintenance of remissions in patients with myelocytic and acute lymphocytic leukemia. Despite their proved clinical importance, 6MP and 6TG have certain therapeutic disadvantages, which have continued to stimulate the search for purine derivatives enhancing therapeutic efficacy. Considerable efforts have been made to prepare other novel mercaptopurine and thioguanine analogs and their nucleosides to improve the antitumor efficacy. The effectiveness of these thiopurines against certain tumor cell lines suggested that some of these mercaptopurine analogs and their nucleosides would be worthy of consideration in order to determine whether they exert a more selective effect against neoplastic cells than against normal cells or they might be useful in patients whose disease has become resistant to 6MP or 6TG. This review will focus on mercaptopurine analogs and their nucleosides as antimetabolite agents.

Antimetabolites, Antineoplastic↗
PubMed2006

Severe ventricular dysrhythmias and silent ischemia during infusion of the antimetabolite 5-fluorouracil and cis-platin.

The antimetabolite 5-fluorouracil is frequently used in the therapy of various malignancies. Cardiotoxicity has frequently been described during treatment, but there is no common agreement on the need to perform cardiovascular monitoring of patients during 5-fluorouracil administration. We report the case of a young patient with an head-neck cancer on whom a continuous electrocardiogram recording was performed, documenting serious ventricular dysrhythmias in the presence of myocardial ischemia during 5-fluorouracil and cis-platin infusion.

Adult↗
PubMed1995

Heat-stabilized albumin microspheres as a sustained drug delivery system for the antimetabolite, 5-fluorouracil.

The aim of this investigation was to study the release behaviour of heat-stabilized albumin microspheres with entrapped 5-Fluorouracil (5-FU) in vitro, and determine the organ distribution in vivo, for potential application in the treatment of ovarian cancer. Additionally, blood chemistry and haematological profiles were composed after intraperitoneal administration of 5-FU-loaded albumin microspheres into adult female Wistar rats. Microspheres with entrapped 5-FU was also added to 10(4) HeLa cells, cultured in Eagles Minimum Essential Medium, and the effects of drug leakage studied. It was found that cell division of the cells was halted before one cell cycle, as demonstrated by the absence of micronuclei and double nuclei. Blood chemistry and haematology indicated mild systemic toxic effects of the drug e.g. bone marrow suppression and liver involvement, reaching a maximum by Day 12 after intraperitoneal administration of 5-FU-microspheres. A return to normal however was observed within 4 weeks. The data suggest that 5-FU-loaded albumin microspheres may be beneficial in reducing the severe side-effects of this antimetabolite, whilst still maintaining therapeutic levels to cause tumour cell death.

Albumins↗
PubMed2000

Alteration of CDKN2/p16 in human astrocytic tumors is related with increased susceptibility to antimetabolite anticancer agents.

A slowly proliferating cell fraction in tumors shows reduced sensitivity to cell cycle-dependent anticancer agents. To understand the molecular basis of drug resistance observed in brain tumors, we examined the relationship between alteration of p16, a cyclin dependent kinase inhibitor whose functions are frequently lost in many human gliomas, and chemosensitivity of tumor cells to various kinds of anticancer agents. Alterations of the p16 gene that include mutation(s) and homozygous deletion as well as p16 protein expression level, were examined in 56 specimens of astrocytic tumors. Their in vitro chemosensitivities to 30 kinds of anticancer agents were analyzed with flow cytometry which detects drug-induced cell death. We found that the alterations were correlated with increased sensitivity to antimetabolite anticancer agents but not with other kinds of agents, including alkylating agents, antibiotics, topoisomerase inhibitors and antimicrotubule agents. The present results suggest that p16 plays a role in determining chemosensitivity of brain tumors, depending on pharmacological mechanisms of anticancer agents. Proper understanding of the molecular machinery which regulates the chemosensitivity may contribute to the choice of anticancer agents for individual patients.

Antimetabolites, Antineoplastic↗
PubMed1985

7-Hydroxyguanine, a novel antimetabolite from a strain of Streptomyces purpurascens. I. Taxonomy of producing organism, fermentation, isolation and biological activity.

Strain A-347, an actinomycete isolated from a soil sample, was found to produce a new antimetabolite, 7-hydroxyguanine. The aerial mycelium formed spiral spore chains with spiny spore surface. The chemical composition of strain A-347 indicated that it was an actinomycete of cell wall Type I. From its morphological, cultural, physiological characteristics and direct comparison with the type culture, this strain was classified as Streptomyces purpurascens. 7-Hydroxyguanine was purified from the broth filtrate by ion exchange chromatography and crystallized from hot 2 M NH4OH. 7-Hydroxyguanine inhibited the growth of experimental tumors such as L1210 leukemia.

Animals↗
PubMed1999

Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview.

Folylpoly-gamma-glutamate synthetase (FPGS) catalyzes the addition of several equivalents of glutamic acid to the gamma-carboxyl group in the side chain of folate cofactors and analogs. Folylpoly-gamma-glutamate synthetase has three functions in folate homeostasis in mammals: polyglutamation prevents efflux of folate cofactors from the cell, it increases the binding of folate cofactors to some of the enzymes of folate interconversion and biosynthesis, and it appears to allow the accumulation of folates in the mitochondria that are required for glycine synthesis. The efficient substrate activity of the newer generations of tetrahydrofolate analogs results in levels of intracellular accumulation of cytotoxic drug in any cell expressing FPGS in which the enzyme activity is not suppressed by feedback, and the binding of folate inhibitors of thymidylate synthase and glycinamide ribonucleotide formyltransferase is substantially increased by polyglutamation. Resistance to these drugs appears to be most frequently due to mutations that change the level of polyglutamation of parent compound, a clear indication of the centrality of the process to the cytotoxicity of these drugs. Folylpoly-gamma-glutamate synthetase is widely expressed in human tumors and is tightly linked either to proliferation or to a lack of differentiation. The cytotoxicity of both thymidylate synthase and purine inhibitors requires continued inhibition of target for greater than one generation time, so that the integrative function of FPGS adds considerably to the efficiency of folate antimetabolites.

Animals↗
PubMed1999

[The use of antimetabolites in the treatment of glaucoma].

Many adjunctive therapies have been proposed to increase the success and prevent or reduce the incidence of complications associated with filtering surgery. Intraoperative or postoperative use of an antimetabolite has found a place as adjunctive therapy for eyes with otherwise pour prognosis following glaucoma filtering surgery.

Antimetabolites↗