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Archivum Immunologiae Et Therapiae... 19942-Chloro-2'-deoxyadenosine (CdA) is a new antimetabolite with very promising effect in the treatment of chronic lymphoproliferative diseases. It has also been shown to... (Review)
Review
2-Chloro-2'-deoxyadenosine (CdA) is a new antimetabolite with very promising effect in the treatment of chronic lymphoproliferative diseases. It has also been shown to have good activity in acute myelogenous leukemia in children. CdA induces DNA single strand breaks and poly(ADP)-ribosylation, apoptosis and is cytotoxic to non-proliferating as well as proliferating cells. Earlier, CdA has only been given as continuous infusion. Recently, however, pharmacokinetic studies have shown that the bioavailability of oral CdA is 50% and of s.c. injection 100%. Furthermore, studies of the intracellular pharmacokinetics shows that there is a prolonged retention of its nucleotide metabolites supporting intermittent dosing.
Topics: Antimetabolites, Antineoplastic; Cladribine; Humans; Lymphoproliferative Disorders
PubMed: 7503639
DOI: No ID Found -
Biochemical Pharmacology Dec 1965
Topics: Alanine; Amides; Animals; Antimetabolites; Escherichia coli; Female; Fetus; Glutamates; Glutamine; Mice; Pregnancy; Pregnancy, Animal; Proline
PubMed: 5326298
DOI: 10.1016/0006-2952(65)90283-2 -
Modern Treatment Sep 1966
Review
Topics: Adrenal Cortex Hormones; Antimetabolites; Humans; Infections
PubMed: 5330755
DOI: No ID Found -
The Journal of Antibiotics Feb 1986
Topics: Animals; Anti-Bacterial Agents; Antimetabolites; Chemical Phenomena; Chemistry; Chickens; Magnetic Resonance Spectroscopy; Pseudomonas aeruginosa; Serine; Streptomyces; Threonine
PubMed: 3082841
DOI: 10.7164/antibiotics.39.304 -
Ophthalmology Oct 2008To compare the relative effectiveness and side effect profiles of antimetabolite drugs in the treatment of noninfectious ocular inflammation. (Comparative Study)
Comparative Study
PURPOSE
To compare the relative effectiveness and side effect profiles of antimetabolite drugs in the treatment of noninfectious ocular inflammation.
DESIGN
Retrospective cohort study.
PARTICIPANTS
A total of 257 patients with inflammatory eye disease seen in a single-center, academic practice and treated with an antimetabolite as a first-line immunosuppressive agent from 1984 to 2006.
METHODS
Data recorded included demographics, antimetabolite and prednisone doses, use of other immunosuppressive drugs, response to therapy, and side effects associated with drug use.
MAIN OUTCOME MEASURES
Ability to control ocular inflammation and to taper prednisone to
RESULTS
Ninety patients with inflammatory eye disease were treated with methotrexate, 38 patients were treated with azathioprine, and 129 patients were treated with mycophenolate. Uveitis accounted for the majority of the diagnoses (67%, 66%, and 68% for methotrexate, azathioprine, and mycophenolate, respectively), followed by scleritis (23%, 18%, 17% for methotrexate, azathioprine, and mycophenolate, respectively). The median time to treatment success was 4.0, 4.8, and 6.5 months for the mycophenolate, azathioprine, and methotrexate treatment groups, respectively (P = 0.02, log-rank test). The incidence of side effects was higher in the azathioprine group (0.29/person-year [PY]) compared with patients treated with methotrexate (0.14/PY) and mycophenolate (0.18/PY). More patients discontinued the drug because of side effects in the azathioprine group (0.24/PY vs 0.09/PY for the methotrexate group and 0.09/PY for the mycophenolate mofetil group).
CONCLUSIONS
These data suggest that the time to control of ocular inflammation is faster with mycophenolate than with methotrexate. Azathioprine therapy has a higher rate of treatment-related side effects compared with the other 2 agents.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimetabolites; Azathioprine; Child; Female; Glucocorticoids; Humans; Inflammation; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Scleritis; Uveitis
PubMed: 18579209
DOI: 10.1016/j.ophtha.2008.04.026 -
Nucleosides, Nucleotides & Nucleic Acids 2014Antimetabolites are the most widely used and most efficacious group of anticancer drugs. Antimetabolites are also the oldest rationally designed anticancer drugs,... (Review)
Review
Antimetabolites are the most widely used and most efficacious group of anticancer drugs. Antimetabolites are also the oldest rationally designed anticancer drugs, targeted against RNA and DNA, and can, therefore, be considered as the first generation of targeted drugs. Unfortunately, resistance often develops, leading to the design of new antimetabolites, which either have a novel mechanism of action, bypass resistance or in combination enhance the effect of other drugs, such as another antimetabolite, other DNA, or protein kinase targeted anticancer drugs. Several novel antimetabolites are in clinical development. The cytidine-analog fluorocyclopentenylcytosine (RX-3117) is active in gemcitabine-resistant tumors and is activated by uridine-cytidine-kinase, can be incorporated into RNA and DNA and can downregulate DNA-methyltransferase-1. TAS-114 is a new generation dUTPase inhibitor. dUTPase normally prevents incorporation of dUTP and of the 5FU-nucleotide FdUTP into DNA. However, inhibition of dUTPase will enhance their incorporation, thereby increasing thymine-less cell-death. The formulation TAS-102 (trifluorothymidine and thymidine-phosphorylase-inhibitor) acts by incorporation into DNA and has shown efficacy in tumors progressing on 5FU therapy. Gemcitabine and cytarabine prodrugs were tested in model systems and have entered clinical evaluation. The elaidic-acid prodrugs of gemcitabine (CP-4126, CO101) and cytarabine (elacytarabine) failed in randomized Phase III studies. Two other gemcitabine prodrugs LY2334737 (gemcitabine with a valproic acid at the 5'-position) and NUC1031 (a 5'-arylphosphoamidate prodrug, with a side-chain at the 5'-phosphate) are in early clinical development. In summary, several novel antimetabolites show promise in clinical development, either because of a novel mechanism of action, or clever combination or by innovative prodrug design.
Topics: Animals; Antimetabolites; Drug Discovery; Drug Interactions; Humans; Prodrugs
PubMed: 24940694
DOI: 10.1080/15257770.2014.894197 -
The Journal of Pharmacy and Pharmacology Jan 1957
Topics: Antimetabolites; Humans; Pyrimidines
PubMed: 13398908
DOI: 10.1111/j.2042-7158.1957.tb12255.x -
Die Ophthalmologie Feb 2023Small sponges are used to apply antimetabolites in order to reduce the risk of fibrosis in filtering glaucoma surgery. Due to the posterior location of the filtering... (Review)
Review
Small sponges are used to apply antimetabolites in order to reduce the risk of fibrosis in filtering glaucoma surgery. Due to the posterior location of the filtering bleb in glaucoma drainage implants, there is a risk that the sponges can dislocate in this area and cannot be retrieved after the exposure time has elapsed. We use the "three cherries technique" to minimize the risk. The term "three cherries technique" was coined by us and has not been used before in the literature. The three sponges that are used for mitomycin C application are each connected by single button sutures with a 7.0 vicryl thread. At the end of the application time, the sponges can be quickly removed by pulling the thread.
Topics: Humans; Glaucoma; Filtering Surgery; Glaucoma Drainage Implants; Antimetabolites; Mitomycin
PubMed: 36418563
DOI: 10.1007/s00347-022-01755-8 -
Transplantation Feb 2004Recurrence of hepatitis C virus (HCV) after liver transplantation is almost universal and decreases both graft and patient survival. Medications that alter nucleic acid... (Comparative Study)
Comparative Study
BACKGROUND
Recurrence of hepatitis C virus (HCV) after liver transplantation is almost universal and decreases both graft and patient survival. Medications that alter nucleic acid metabolism, including some common immunosuppressants used in HCV-infected patients, may affect viral replication.
METHODS
Bovine viral diarrhea virus (BVDV) is in the Flaviviridae family and is closely related to HCV. We measured the effect of two immunosuppressants, azathioprine (AZA) and mycophenolate acid (MPA), on both BVDV replication by plaque assay and host-cell replication by flow cytometry. We also compared the effect of ribavirin and AZA on the level of HCV replicon RNA by real-time reverse-transcriptase polymerase chain reaction.
RESULTS
At doses that achieved similar cytotoxicity, AZA decreased BVDV replication 10 times more than MPA. The inhibition of BVDV by AZA occurred at lower doses than the cellular cytotoxicity and did not depend on cytotoxicity. A two-log reduction in viral titers occurred despite blocking the cytotoxicity of AZA by inhibiting ribonucleotide reductase with high concentrations of thymidine. A metabolite of AZA, 6-mercaptopurine, still possessed this antiviral effect, but a metabolite further downstream, 6-thioguanine, did not, even though 6-thioguanine is the metabolite responsible for cellular toxicity. The effect of AZA on a HCV replicon was at least as large as that of ribavirin.
CONCLUSIONS
This report suggests that AZA is a more potent antiviral than MPA for Flaviviridae and may exert a specific antiviral effect on HCV. Additional clinical studies to investigate this previously unanticipated antiviral effect of AZA on HCV in the posttransplant setting are indicated.
Topics: Animals; Antimetabolites; Antiviral Agents; Azathioprine; Cattle; Cell Line; Diarrhea Viruses, Bovine Viral; Dose-Response Relationship, Drug; Hepacivirus; Immunosuppressive Agents; Mercaptopurine; Mycophenolic Acid; Replicon; Ribavirin; Thioguanine; Virus Replication
PubMed: 15084936
DOI: 10.1097/01.tp.0000114610.40412.c6 -
Experimental Eye Research Jul 1999The use of single five-minute applications of antimetabolites during glaucoma filtration surgery has significantly reduced the occurrence of post-operative scarring and...
The use of single five-minute applications of antimetabolites during glaucoma filtration surgery has significantly reduced the occurrence of post-operative scarring and bleb failure. However, surgery for some patients is still unsuccessful, despite the use of antiproliferative agents, due to formation of scar tissue at the drainage site. It is not known if cells growth arrested in the treated area with a single application of antimetabolites influence the activity of adjacent non-treated cells. We hypothesise that the activity of non-treated cells recruited to the wound site may be involved in post-operative scarring. The aim of this study was to investigate the effects of antimetabolite induced cellular growth arrest on cell-cell interactions using in vitro techniques.Tenon's capsule fibroblast cultures were growth arrested by exposure for 5 minutes to mitomycin-C (0.001, 0.01 and 0.1 mg ml-1), 5-fluorouracil (0.25, 2.5 and 25 mg ml-1) or phosphate buffered saline (PBS). Following a period of serum-starvation, conditioned media (CM) were subsequently collected from the cells at intervals up to 29 days post-treatment. Correction for cell number was made prior to supplementation of serum-free medium with CM. CM were assessed for ability to support or inhibit normal non-treated fibroblast proliferation, migration and collagen contraction. Conditioned media collected from cells growth arrested with MMC or 5FU stimulated normal fibroblast proliferation, migration and collagen contraction in excess of non-conditioned serum-free medium. Peaks of fibroblast activity in CM differed according to which drug and concentration had originally been given to the treated cells. This study has demonstrated that CM collected from fibroblasts treated for 5 minutes with a range of concentrations of antimetabolites can differentially influence normal non-treated fibroblast activity. This in vitro data suggests that despite entering growth arrest, fibroblasts may still influence the behaviour of other cells via soluble mediators. They may have implications in the clinical setting, in that it may not be sufficient to suppress proliferation alone to prevent fibroblast behaviour associated with scarring after glaucoma filtration surgery.
Topics: Antimetabolites; Cell Communication; Cell Culture Techniques; Cell Division; Chemotaxis; Collagen; Connective Tissue Cells; Culture Media, Conditioned; Dose-Response Relationship, Drug; Eye; Fibroblasts; Humans; Mitomycin; Nucleic Acid Synthesis Inhibitors
PubMed: 10375456
DOI: 10.1006/exer.1999.0684