SEARCH · PubMed Health

Results for “ANTIMETABOLITES”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources

PubMed1996

Influence of both salvage and DNA damage response pathways on resistance to chemotherapeutic antimetabolites.

The resistance of 3 human embryo fibroblast cell lines to the antimetabolites methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA) and 5-fluorouracil (5-FU) has been studied. The cell lines were of common genetic origin, all originating from the normal KMS parental cell line, which was irradiated with 60Co to produce the immortalised derivative KMST which, in turn, was transfected with an activated N-ras oncogene to produce the tumourigenic KN-NM cell line. Previous work from this group, using dialysed versus nondialysed serum, has provided evidence for the involvement of salvage pathways of purine and pyrimidine biosynthesis in the increased resistance to antimetabolites of those cell lines (KMST and KN-NM) tending towards increased tumourigenicity. The present study has extended this work by using the nucleoside and nucleobase transport inhibitor dipyridamole, to further assess the contribution of the salvage pathways to the increased cellular resistance to the three antimetabolites. The salvage pathways were found to contribute to the resistance of cell lines to PALA and MTX, but had no effect on the resistance to 5-FU. The addition of excess uridine in the case of PALA, and hypoxanthine plus thymidine in the case of MTX, could be used to "rescue" cells from the effects of dipyridamole-induced salvage pathway inhibition. The data will be discussed in relation to 1. the effect of limited substrate availability, 2. the induction of DNA damage and DNA damage-response pathways, and 3. DNA-damage protection by the salvage pathways of purine and pyrimidine biosynthesis.

Antimetabolites↗

PubMed1992

Effects of glucose and fat antimetabolites on norepinephrine turnover in rat hypothalamus and brainstem.

Rats were injected acutely with antimetabolites of either glucose (2 deoxy-D-glucose, 2DG), fat (methylpalmoxirate, MP or mercaptoacetate, MAC), or the combination of these agents, in dosages known to stimulate food intake. Norepinephrine (NE) turnover in hypothalamus and brainstem was determined after these treatments by the method of synthesis inhibition. Glucoprivation (2DG) increased NE turnover in hypothalamus, confirming previous studies. Fat antimetabolites alone had no effect on NE turnover, nor did a peripherally-acting fructose antimetabolite. Combination of MP and 2DG, but not MAC and 2DG, produced a greater NE turnover than 2DG alone. These data suggest that peripheral signals of metabolic emergency do not activate brain NE systems, except when these systems are already activated by an ongoing cerebral metabolic emergency. The role of hypothalamic NE in metabolic integration of feeding is discussed, and possible hemispheric differences.

Animals↗

PubMedDate not supplied

Effect of antimetabolite drugs of nucleotide metabolism on the anti-human immunodeficiency virus activity of nucleoside reverse transcriptase inhibitors.

A number of attempts are currently underway to combine antimetabolite drugs of nucleotide metabolism with a nucleoside reverse transcriptase inhibitor (NRTI) targeting human immunodeficiency virus (HIV) to improve the antiviral efficacy of the NRTIs and to better control HIV drug resistance. Hydroxyurea, a ribonucleotide reductase inhibitor, is currently combined with the NRTI didanosine (2',3'-dideoxyinosine) in clinical trials. However, other cellular target enzymes, including thymidylate synthase, inosinate dehydrogenase, cytidine-5'-triphosphate synthetase, and other enzymes from the de novo nucleotide biosynthesis pathway, can also be considered to potentiate the antiviral action of NRTIs. The underlying reasons for the potentiation of the antiviral activity of the NRTIs by antimetabolite drugs of nucleotide metabolism can be multiple. Decreased endogenous 2'-deoxynucleoside-5'-triphosphate (dNTP) pools result in a better competition of the NRTI (as its triphosphate derivative), with the dNTPs for the virus-encoded reverse transcriptase to be recognized as a substrate for the DNA polymerization reaction and subsequently to be incorporated into the growing viral DNA chain. Also, an increased metabolism (phosphorylation) of the NRTI by stimulatory enzyme feedback mechanisms may result in the production of higher levels of NRTI triphosphate. Thus, higher intracellular ratios of NRTI-triphosphate/dNTP created by well-defined combinations of NRTIs and antimetabolite drugs enable a more profound inhibitory effect of the NRTI against the reverse transcriptase (and thus, against the virus) and a better suppression of resistant (mutant) virus strains. A profound evaluation of this relatively new concept in the clinical setting will reveal whether this approach will establish a place in future treatment modalities of HIV infections.

Antimetabolites↗

PubMedDate not supplied

Basis for effective combination cancer chemotherapy with antimetabolites.

Most current chemotherapy regimens for cancer consist of empirically designed combinations, based on efficacy and lack of overlapping toxicity. In the development of combinations, several aspects are often overlooked: (1) possible metabolic and biological interactions between drugs, (2) scheduling, and (3) different pharmacokinetic profiles. Antimetabolites are used widely in chemotherapy combinations for treatment of various leukemias and solid tumors. Ideally, the combination of two or more agents should be more effective than each agent separately (synergism), although additive and even antagonistic combinations may result in a higher therapeutic efficacy in the clinic. The median-drug effect analysis method is one of the most widely used methods for in vitro evaluation of combinations. Several examples of classical effective antimetabolite-(anti)metabolite combinations are discussed, such as that of methotrexate with 6-mercaptopurine or leucovorin in (childhood) leukemia and 5-fluorouracil (5FU) with leucovorin in colon cancer. More recent combinations include treatment of acute-myeloid leukemia with fludarabine and arabinosylcytosine. Other combinations, currently frequently used in the treatment of solid malignancies, include an antimetabolite with a DNA-damaging agent, such as gemcitabine with cisplatin and 5FU with the cisplatin analog oxaliplatin. The combination of 5FU and the topoisomerase inhibitor irinotecan is based on decreased repair of irinotecan-induced DNA damage. These combinations may increase induction of apoptosis. The latter combinations have dramatically changed the treatment of incurable cancers, such as lung and colon cancer, and have demonstrated that rationally designed drug combinations offer new possibilities to treat solid malignancies.

Antimetabolites, Antineoplastic↗

PubMed1976

Glucose antimetabolites and hunger (theoretical article).

A decrease in the cellular utilization of glucose produced by several glucose antimetabolites and especially by 2 deoxy-D-glucose considerably stimulates food intake. An analysis of this phenomenon is presented in terms of the available experimental evidence. Experiments in which glucose antimetabolites have been administered so as to influence selectively the central and peripheral glucosensitive loci suggest a possible mechanism for the action of the substances. The mechanisms by which glucose antimetabolites and exogenous insulin induce cellular glucoprivation and the subsequent changes in food intake are compared and discussed.

Animals↗

PubMed1985

Nutritional requirements of Plasmodium falciparum in culture. II. Effects of antimetabolites in a semi-defined medium.

A semi-defined minimal medium, in which pantothenic acid is the only vitamin, was used to culture Plasmodium falciparum for the analysis of antimetabolite drugs. Analogs of riboflavin, nicotinamide, pyridoxine, and thiamin inhibited the growth of this parasite; for each drug, effects were much more pronounced after 96 h of exposure compared to 48 h. The most potent drug examined was 8-methylamino-8-desmethyl riboflavin (IC50 value approximately 1.0 X 10(-10) M at 96 h). Avidin, a protein which complexes and thus inactivates biotin, did not affect parasite viability. Other antimalarial drugs, including chloroquine and quinine derivatives and antibiotics, were equipotent in the minimal medium and in RPMI 1640. Four strains of P. falciparum showed only minor differences in sensitivity to these antimetabolites. The use of prolonged drug exposure times and a vitamin-depleted medium allowed the preliminary characterization of antimalarial antimetabolites in vitro.

Animals↗

PubMed2003

Dynamics of subgenomic hepatitis C virus replicon RNA levels in Huh-7 cells after exposure to nucleoside antimetabolites.

Treatment with antimetabolites results in chemically induced low nucleoside triphosphate pools and cell cycle arrest in exponentially growing cells. Since steady-state levels of hepatitis C virus (HCV) replicon RNA were shown to be dependent on exponential growth of Huh-7 cells, the effects of antimetabolites for several nucleoside biosynthesis pathways on cell growth and HCV RNA levels were investigated. A specific anti-HCV replicon effect was defined as (i). minimal interference with the exponential cell growth, (ii). minimal reduction in cellular host RNA levels, and (iii). reduction of the HCV RNA copy number per cell compared to that of the untreated control. While most antimetabolites caused a cytostatic effect on cell growth, only inhibitors of the de novo pyrimidine ribonucleoside biosynthesis mimicked observations seen in confluent replicon cells, i.e., cytostasis combined with a sharp decrease in replicon copy number per cell. These results suggest that high levels of CTP and UTP are critical parameters for maintaining the steady-state level replication of HCV replicon in Huh-7 cells.

Antimetabolites↗

PubMed1996

Antimetabolite interactions with epidermal growth factor.

Antimetabolites such as 5-fluorouracil and mitomycin C are known to delay wound healing. Epidermal growth factor (EGF) has been shown to accelerate corneal epithelial wound healing. This study was designed to investigate the effects of EGF on corneal epithelial healing that has been modified by antimetabolite treatment. New Zealand White rabbits were pretreated with either saline (controls) or 5-fluorouracil (5FU) injected subconjunctivally, or mitomycin C (MMC) applied topically. Circular anterior stromal wounds were created, followed by a 6-hour perfusion of normal saline or 50 micrograms/ml of EGF. Subconjunctival saline or 5FU, or topical MMC treatments were continued after wounding for a total of 6 days. Corneas were photographed and quantitative morphometry of the wound site was performed. Compared with saline controls, MMC significantly delayed wound healing (P < 0.05) whereas 5FU did not (P > 0.05). Compared with 5FU, MMC significantly delayed wound healing with either normal saline or EGF perfusion (P < 0.05). In the presence of either 5FU or MMC, EGF perfusion had no significant effect on the corneal wound-healing rate (P > 0.05). Corneal wound healing is not affected by subconjunctivally injected 5FU while it is delayed by topically applied MMC. EGF treatment does not overcome the inhibitory effects of MMC. EGF therapy may not be useful in the treatment of complications related to antimetabolite therapy.

Administration, Topical↗

PubMed2006

The relationship of premature mitosis to cytotoxicity in response to checkpoint abrogation and antimetabolite treatment.

Inhibition of one or both of the checkpoint kinases, Chk1 and Chk2, has been proposed as a strategy for improving the efficacy of cytotoxic chemotherapeutic agents in tumor cells. Previous studies have demonstrated that Chk1 inhibition potentiates the cytotoxicity of chemotherapeutic agents in a variety of systems. We designed a study to test whether the simultaneous depletion of Chk1 and Chk2 would sensitize cells to FdUrd- and gemcitabine-induced cytotoxicity to a greater extent than Chk1 depletion alone and to determine the contribution of premature mitosis to cytotoxicity. We found that RNAi-mediated Chk1 depletion enhanced FdUrd- and gemcitabine-mediated cytotoxicity (2- to 3-fold) in Panc-1 and SW620 cells. Furthermore, enhanced cytotoxicity by Chk1 depletion was accompanied by inhibition of FdUrd- or gemcitabine-induced Cdc25A degradation and induction of premature mitotic entry in drug-treated cells. The simultaneous depletion of Chk1 and Chk2 inhibited Cdc25A degradation, induced premature mitotic entry and enhanced cytotoxicity in response to FdUrd and gemcitabine to a similar extent as Chk1 depletion alone. These results imply that Chk2 inhibition has no immediate consequence on survival or cell cycle progression in tumor cells treated with antimetabolites, regardless of their Chk1 status. In addition, these results suggest that premature mitotic entry is a qualitative marker for enhanced antimetabolite-induced cytotoxicity by Chk1 inhibition. The finding that Chk1 inhibition significantly enhanced antimetabolite-induced cytotoxicity supports further investigation and the development of more specific Chk1 inhibitors for use in the clinic.

Antimetabolites, Antineoplastic↗

PubMed2002

[Antimetabolites in glaucoma surgery--long-term results].

PURPOSE: To observe the long term success of antimetabolites used in glaucoma filtering surgery in eyes with high risc of failure. MATERIAL AND METHOD: Two groups of patients undergone trabeculectomy with the use of antimetabolites 5-Fluorouracil (5-FU) and Mitomycin C (MMC) are included in this retrospective study. 5-FU was administered postoperatively 1-10 times in the dose of 5 mg/ml in subconjunctival injection on 32 eyes. Follow up time ranged from 8 months to 9 years. Mitomycin C was administered intraoperatively in the dose of 0.2 mg/ml, on subconjunctival sponge with application time from 3 to 5 minutes on 15 eyes. Follow up time ranged from 7 month to 4.5 years. RESULTS: Intraocular pressure (IOP) before operation with the use of 5-FU was in average 28.8 mmHg (22-50 mmHg) at the end of therapy with 5-FU was 17.6 mmHg (10-30 mmHg) and in the last examination was on average 19.5 mmHg (14-28 mmHg). IOP before operation with the use of MMC was in average 30.3 mmHg (22-40 mmHg), the seventh day after administration of MMC 12.7 mmHg (6-20 mmHg) and in the last examination was in average 18 mmHg (9-28 mmHg). During the long term observation of IOP values in the 5-FU group there was 79.2% success and in the MMC group there was 83.3% success (IOP up to 20 mmHg with or without therapy). Decrease of IOP was statistically significant. CONCLUSION: Antimetabolites improve the success of filtering surgery in high risc glaucomas. The long term follow up shows that failure of filtration in these types of glaucomas is still a serious clinical problem.

Adult↗

PubMed1992

[Clinical pharmacology of anticancer agents (Part 4). Antimetabolites (1)].

1. Pharmacodynamics and pharmacokinetics of antimetabolites. Antimetabolites are administered in the form of a base or its riboside, which is incorporated into the cell and converted to an active or inactive metabolite. The active metabolite remain in the cell inhibiting the enzymes to catalyze nucleotide synthesis for nucleotide triphosphate formation, but the inactive metabolites are rapidly excreted out of the cell. The inhibitory effect of antimetabolites on nucleotide formation is correlated with factors, such as maintenance of drug blood level, incorporation of the drug into the cell, activation and inactivation of the drug, affinity of the active form to the corresponding enzyme, and change in pool size of the intermediate metabolites in nucleotide synthesis. The salvage synthesis occurring at the higher level of the enzymes catalyzing nucleotide synthesis to counteract the inhibition by the drug is also correlated with the nucleotide formation. II. Pyrimidine antagonists 1. Cytosine arabinoside (ara-C) and its derivatives Ara-C is rapidly converted to ara-CTP and ara-U. The former remains in the cell and inhibits DNA polymerase, but the latter is excreted rapidly out of the cell. A small portion of ara-C is incorporated into DNA, which results in the degradation of DNA as demonstrated by reduced sedimentation of bulk DNA in alkaline sucrose gradient centrifugation and the ladder DNA fragmentation with a minimum fragment of approximately 180 base pairs and its conjugates in agarose gel electrophoresis. Behenoyl ara-C (BHAC) is highly lipophilic and highly distributed in the erythrocyte stroma and membrane fraction of leukocytes after iv infusion. The incorporated BHAC is released after the plasma BHAC level decreases, which suggests that erythrocytes can be a drug reservoir after iv infusion. Therefore, severe anemia should be treated before BHAC chemotherapy for longer maintenance of the plasma BHAC level. 2. 5-Fluorouracil (5-FU) and its derivatives Activation of 5-FU in the cells is metabolized by uracil metabolizing enzymes to FUMP and FdUMP. FUMP is further metabolized to FdUMP and is also incorporated to RNA. FdUMP produces a ternary complex with thymidylate synthetase and leucovorin; subsequently, conversion of dUMP to dTMP is strongly inhibited. Thus, FUMP and FdUMP inhibit RNA and DNA metabolism, respectively. Enzyme activity during 5-FU metabolism and consequently the degree of inhibition of DNA and RNA syntheses markedly differ with the tumor cell species. This should be taken into consideration when performing chemotherapy of malignancies.

Animals↗

PubMed1977

Detection and microbiologic assays of antimetabolites.

The biochemical considerations applicable in the detection of new antimetabolites are very similar to those used in developing microbiologic assays for these drugs. An in vitro system for detection of antimetabolites was developed based on different sensitivities to such drugs of bacteria cultivated in complex versus completely synthetic media. A number of new antimetabolites of amino acids, vitamins, and purines or pyrimidines were isolated and microbiologic assays for these drugs were developed. As an example of the technology utilized and possibilities available, an assay for cytosine arabinoside was described. It can detect 0.5-microgram/ml concentrations of this drug even in the presence of other antitumor or antibacterial antibiotics.

Anti-Bacterial Agents↗

PubMed1979

In vitro system for detection of antimetabolites of specific amino acids.

An in vitro system was developed to detect antimetabolites in fermentation liquors of soil microorganisms. This system effectively uncovers antimetabolites of purines and pyrimidines and of selected amino acids with established differences in their biosynthesis by normal cells versus certain malignant cells. Currently these amino acids include: L-asparagine, L-aspartic acid, L-glutamine, L-cysteine (cystine), L-methionine, L-arginine, L-histidine, L-tyrosine, L-phenylalanine, L-tryptophan, L-threonine, and L-serine. It is expected that these antimetabolites could be useful either alone or in combination with specific depleting enzymes in the treatment of malignancies where such an imbalance was established.

Amino Acids↗

PubMed1995

Clinical resistance to antimetabolites.

Antimetabolites are rational agents with specific S-phase and enzyme targets. Low levels of target enzymes in tumors are associated with innate drug sensitivity, and the general requirement for transport and metabolic activation of antimetabolites creates several loci of acquired drug resistance. Pharmacodynamic studies of TS inhibition after fluoropyrimidines clearly can predict for tumor sensitivity and response to fluoropyrimidine-based therapy or identify factors related to resistance, and ara-dCTP levels in leukemic cells can be useful for refined dosing of araC. Powerful new DHFR and TS directed agents are in advanced levels of clinical evaluation, and purine analogues directed against adenosine deaminase are newly available for treatment of indolent lymphomas. Progress in analysis of tumors, such as PCR techniques to study gene expression or immunostaining of target enzymes, offer increasing promise for individualization of patient selection. Increased experience with biochemical modulators, including biologic response modifiers, has opened the possibility for selective attack on specific mechanisms of drug resistance. Sophisticated pharmacokinetic modeling and pharmacogenetic testing of metabolic phenotypes can now be done to achieve optimal dosing with less risk of toxicity. Considerations of ultimate genetic mechanisms of antimetabolite effects, especially by programmed cell death, and relationships to mechanisms of cell cycle regulation offer exciting rationales for future drug development.

Antimetabolites, Antineoplastic↗

PubMed1975

Effects of thiamine antagonists on nerve conduction. I. Actions of antimetabolites and fern extract on propagated action potentials.

To assess the hypothesis that thiamine is directly involved in the permeability changes at the sodium channel during nerve conduction, the effects of thiamine antagonists on lobster giant axon resting and action potentials were determined. Thiamine antimetabolites, in millimolar concentrations, reversibly decreased the maximum rate of rise and amplitude of the action potential while increasing its duration. In particular, thiamine tert-butyl disulfide (TTBD) elicited the formation of pronounced shoulders during repolarization, lengthening the action potential by 2-50 times, depending on dose. Antimetabolites also depolarized the resting membrane, but this change was poorly reversible and may indicate a dual mechanism for antimetabolite action. An extract of the fern, Pteris aquilina, reversibly decreased the maximum rate of rise of the action potential and depolarized the resting potential. It also elevated and prolonged the action potential after-depolarization, sometimes causing repetitive activity. The strength of these actions was correlated with the antithiamine potency of the extract, and was diminished by addition of thiamine to the extract.

Action Potentials↗

PubMed1986

Combined therapy of polyamine antimetabolites and antitumor drugs for human gastric cancer xenotransplanted into nude mice.

Antitumor therapies using polyamine antimetabolites combined with 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3(2-chloroethyl)-3-nitrosourea (ACNU) or fluorinated pyrimidines for human gastric cancer xenotransplanted into nude mice were studied to determine inhibiting post-therapeutic regrowth of the tumor after cessation of antitumor treatments with polyamine antimetabolites alone. ACNU 20 mg/kg, fluorinated pyrimidine, 5-FU 52.8 mg/kg and 5'-deoxy-5-fluorouridine (5'-DFUR) 100 mg/kg as well as polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) 1000 mg/kg and methylglyoxal-bis-guanylhydrazone (MGBG) 50 mg/kg were given intraperitoneally for 5 successive days. When DFMO and MGBG were combined with ACNU, the post-therapeutic regrowth was definitely inhibited, while combined treatments with 5-FU or 5'-DFUR did not inhibit the regrowth. Post-therapeutic DNA biosynthesis was suppressed in mice given DFMO, MGBG plus ACNU. On the contrary, in mice treated with DFMO, MGBG plus 5-FU or 5'-DFUR, suppression of DNA biosynthesis was not observed. Tumor tissue spermine levels in the DFMO, MGBG plus 5-FU or 5'-DFUR group remained unchanged, compared to those in the DFMO + MGBG group. In mice given DFMO, MGBG plus ACNU, however, spermine levels were markedly depressed; and the ACNU alone depressed also the tissue spermine levels. These different results between nitrosourea and fluorinated pyrimidines may relate to mechanisms of action of these antitumor drugs.

Animals↗

PubMed1986

Analysis of 5-fluoro-2'-deoxycytidine and 5-trifluoromethyl-2'-deoxycytidine and their related antimetabolites by high-performance liquid chromatography.

An isocratic, ion-paired, reversed-phase high-performance liquid chromatography technique for the quantitative determination of 5-fluoro-2'-deoxycytidine (FdCyd) and 5-trifluoromethyl-2'-deoxycytidine (F3methyldCyd) and their related antimetabolites is described. Extraction and purification of these compounds from DNA, RNA, and free pools is reviewed diagrammatically. Total analysis time including quantitation of DNA and RNA primary constituents is 45 min. Average combined recoveries for prodrugs and antimetabolites is above 90% with standard deviations of 0.07 and 0.58 and average precisions of 5.51 and 8.30% for FdCyd and F3methyldCyd, respectively. Average coefficients of variation were 3.8 +/- 0.5% for FdCyd and 7.7 +/- 1.0% for F3methyldCyd. Limits of detection were approximately 1 pmol for unlabelled prodrugs and antimetabolites. FdCyd, when generally tritiated with a specific activity of 18 Ci/mmol, was detected in the 5 X 10(-15)-20 X 10(-15) mol (fmol) range depending on sample condition.

Buffers↗

PubMed2004

The structure of the pantothenate kinase.ADP.pantothenate ternary complex reveals the relationship between the binding sites for substrate, allosteric regulator, and antimetabolites.

Pantothenate kinase catalyzes the first step in the biosynthesis of coenzyme A, the major acyl group carrier in biology. In bacteria, regulation of pantothenate kinase activity is a major factor in controlling intracellular coenzyme A levels, and pantothenate analogs are growth-inhibiting antimetabolites. We have extended the structural information on Escherichia coli pantothenate kinase by determining the structure of the enzyme.ADP. pantothenate ternary complex. Pantothenate binding induces a significant conformational change in amino acids 243-263, which form a "lid" that folds over the open pantothenate binding groove. The positioning of the substrates suggests the reaction proceeds by a concerted mechanism that involves a dissociative transition state, although the negative charge neutralization of the gamma-phosphate by Arg-243, Lys-101, and Mg(2+) coupled with hydrogen bonding of the C1 of pantothenate to Asp-127 suggests different interpretations of the phosphoryl transfer mechanism of pantothenate kinase. N-alkylpantothenamides are substrates for pantothenate kinase. Modeling these antimetabolites into the pantothenate active site predicts that they bind in the same orientation as pantothenate with their alkyl chains interacting with the hydrophobic dome over the pantothenate pocket, which is also accessed by the beta-mercaptoethylamine moiety of the allosteric regulator, coenzyme A. These structural/biochemical studies illustrate the intimate relationship between the substrate, allosteric regulator, and antimetabolite binding sites on pantothenate kinase and provide a framework for studies of its catalysis and feedback regulation.

Allosteric Regulation↗