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Journal of Clinical Oncology : Official... Sep 2007Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and... (Review)
Review
Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.
Topics: Animals; Antimetabolites, Antineoplastic; Combined Modality Therapy; Humans; Neoplasms; Radiation-Sensitizing Agents
PubMed: 17827452
DOI: 10.1200/JCO.2007.11.5287 -
Future Oncology (London, England) Jan 2016TAS-102, a novel antimetabolite combination chemotherapy agent, consists of a rediscovered antimetabolite agent, trifluorothymidine (trifluridine) combined with the... (Review)
Review
TAS-102, a novel antimetabolite combination chemotherapy agent, consists of a rediscovered antimetabolite agent, trifluorothymidine (trifluridine) combined with the metabolic inhibitor of thymidine phosphorylase, tipiracil, in a 1:0.5 molar ratio. Mechanism of action studies suggest that this agent works by incorporation into DNA. Both preclinical and clinical studies demonstrate that this agent is noncross-resistant with 5-fluorouracil. Tipiracil may also have antiangiogenic effects through inhibition of thymidine phosphorylase. Recent randomized Phase II and III trials demonstrate clinical activity (improved progression-free survival, time to decrease in performance status, prolonged overall survival) in metastatic colorectal cancer refractory to all standard agents. Monotherapy with TAS-102 has now been approved for this indication in Japan and in the USA.
Topics: Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Clinical Trials as Topic; Colorectal Neoplasms; Drug Combinations; Drug Resistance, Neoplasm; Fluorouracil; Humans; Neoplasms; Pyrrolidines; Thymine; Treatment Outcome; Trifluridine; Uracil
PubMed: 26616466
DOI: 10.2217/fon.15.276 -
Medwave Jan 2018Trabeculectomy is considered the standard for glaucoma surgery. Postoperative scarring is one the factors associated with surgery failure. Different antimetabolites have... (Comparative Study)
Comparative Study Review
INTRODUCTION
Trabeculectomy is considered the standard for glaucoma surgery. Postoperative scarring is one the factors associated with surgery failure. Different antimetabolites have been used in order to reduce this risk, particularly 5-fluorouracil and mitomycin C. Although both are considered effective, it is not clear if they are different in terms of success of trabeculectomy and adverse effects.
METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.
RESULTS AND CONCLUSIONS
We identified four systematic reviews including 17 studies overall, of which 12 were randomized trials. We concluded mitomycin C might be more effective in reducing intraocular pressure and increasing qualified success compared to 5-fluorouracil. However, its use might be associated to a higher risk of complications.
Topics: Antimetabolites; Cicatrix; Fluorouracil; Glaucoma; Humans; Intraocular Pressure; Mitomycin; Randomized Controlled Trials as Topic; Trabeculectomy
PubMed: 29351270
DOI: 10.5867/medwave.2018.01.7138 -
Expert Opinion on Investigational Drugs Apr 2019RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The... (Comparative Study)
Comparative Study Review
RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.
Topics: Administration, Oral; Antimetabolites, Antineoplastic; Biological Availability; Cytidine; Deoxycytidine; Humans; Neoplasms; Patient Selection; Gemcitabine
PubMed: 30879349
DOI: 10.1080/13543784.2019.1583742 -
Biopolymers Nov 2002Antimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes.... (Review)
Review
Antimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes. In this review, the recent literature describing investigations of the structural and thermodynamic basis for the anticancer activity of three antipyrimidines [1-beta-D-arabinofuranosyl cytidine (AraC). 2',2'-difluoro deoxycytidine (dFdC), and 5-fluoro-2'-deoxyuridine (FdUrd)] is summarized. Our laboratory, and others, have shown that misincorporation of any of these three antipyrimidines into DNA perturbs the structure and decreases the stability of duplex DNA. These data are useful for rationalizing the effects of antipyrimidine misincorporation on the activities of proteins required for DNA replication and repair such as DNA topoisomerase 1 and DNA polymerases. The studies completed to date and summarized in this review demonstrate the utility of investigations into the structure-function relationships between antipyrimidine-substituted DNA complexed with DNA-modifying proteins for the purpose of understanding the basis for effective antipyrimidine cancer chemotherapy and the future design of novel anticancer drugs.
Topics: Antimetabolites, Antineoplastic; Base Sequence; DNA; DNA Repair; DNA Replication; Humans; Models, Molecular; Neoplasms; Nucleic Acid Conformation; Structure-Activity Relationship; Thermodynamics
PubMed: 12228923
DOI: 10.1002/bip.10214 -
JAMA Ophthalmology Dec 2019
Topics: Adrenal Cortex Hormones; Antimetabolites; Humans; Immunosuppressive Agents; Inflammation; Methotrexate; Mycophenolic Acid; Uveitis
PubMed: 31503274
DOI: 10.1001/jamaophthalmol.2019.3964 -
International Journal of Antimicrobial... Apr 2019Increased antibacterial resistance jeopardizes current therapeutic strategies to control infections, soliciting the development of novel antibacterial drugs with new...
Increased antibacterial resistance jeopardizes current therapeutic strategies to control infections, soliciting the development of novel antibacterial drugs with new mechanisms of action. This study reports the discovery of potent and selective antistaphylococcal activity of 3-bromopyruvate (3BP), an antimetabolite in preclinical development as an anticancer drug. 3BP showed bactericidal activity against Staphylococcus aureus, with active concentrations comparable with those reported to be effective against cancer cells. In contrast, no relevant activity was observed against other ESKAPE bacteria (Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.). The antistaphylococcal activity of 3BP was confirmed using a panel of human and veterinary strains, including multi-drug-resistant isolates. 3BP showed highest antibacterial activity under conditions that increase its stability (acidic pH) or promote S. aureus fermentative metabolism (anaerobiosis), although 3BP was also able to kill metabolically inactive cells. 3BP showed synergism with gentamicin, and also disrupted preformed S. aureus biofilms at concentrations only slightly higher than those inhibiting planktonic cells. This study unravels novel antibacterial and antibiofilm activities for the anticancer drug 3BP, paving the way for further preclinical studies.
Topics: Anti-Bacterial Agents; Antimetabolites; Biofilms; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Pyruvates; Staphylococcal Infections; Staphylococcus aureus
PubMed: 30472291
DOI: 10.1016/j.ijantimicag.2018.11.008 -
The Ocular Surface Oct 2022Pterygium is an ultraviolet-related disease characterized by an aberrant, wing-shaped and active wound-healing process. There is nothing quite as disheartening for the... (Review)
Review
5-Fluorouracil in primary, impending recurrent and recurrent pterygium: Systematic review of the efficacy and safety of a surgical adjuvant and intralesional antimetabolite.
Pterygium is an ultraviolet-related disease characterized by an aberrant, wing-shaped and active wound-healing process. There is nothing quite as disheartening for the surgeon or patient as the recurrence of pterygium, and various adjuvants have been studied to ameliorate this. This systematic review provides a comprehensive summary of the efficacy and safety of 5-Fluorouracil (5-FU) as an antimetabolite agent for pterygium management. An appraisal of electronic searches of six databases identified 34 clinical studies reporting recurrence outcomes of 5-FU use in primary, impending recurrent and recurrent pterygia. In vitro and in vivo studies of 5-FU showed dose- and duration-dependent cytostatic and cytotoxic effects in human cells. 5-FU is relatively inexpensive, available, and easy to administer, making it attractive for resource-limited scenarios. However, the published evidence demonstrates a recurrence rate of 11.4-60% with the bare scleral technique, 3.5-35.8% with conjunctival rotational flaps, 3.7-9.6% with conjunctival autografts for intraoperative topical 5-FU, and 14-35.8% for preoperative and intraoperative injections. This suboptimal efficacy brings the role of 5-FU as an adjuvant for pterygium surgery into question and the authors do not recommend its use. In contrast, postoperative intralesional injections of 5-FU to arrest progression in impending recurrent pterygium and true recurrent pterygia were more promising, with success rates of 87.2-100% and 75-100%, respectively. Furthermore, 5-FU as a treatment modality, without surgery, effectively arrested progression in 81.3-96% of primary and recurrent pterygia. Other treatments such as topical and intralesional corticosteroids, cyclosporine and anti-VEGF agents are discussed. Complications of 5-FU increase with higher doses and range from transient and reversible to severe and sight-threatening. For pterygium, 5-FU has a predilection for causing scleral thinning, corneal toxicity, and graft-related complications. Additional study with extended follow-up is needed to elucidate the optimal dose, frequency, duration, and long-term safety of 5-FU injections. If 5-FU is used in the management of pterygium, it should be with caution, in selected patients and with vigilant long-term monitoring.
Topics: Humans; Pterygium; Antimetabolites; Fluorouracil; Recurrence; Conjunctiva; Immunosuppressive Agents; Injections, Intralesional; Follow-Up Studies; Treatment Outcome
PubMed: 35961535
DOI: 10.1016/j.jtos.2022.08.002 -
Protein Science : a Publication of the... Feb 2016The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this... (Review)
Review
The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this essential vitamin. Approximately 13,000 putative transporters of the family have been identified. However, before our work, no structural information was available and even functional data were minimal for this family of membrane proteins. To elucidate the structure and function of the AbgT family of transporters, we recently determined the X-ray structures of the full-length Alcanivorax borkumensis YdaH and Neisseria gonorrhoeae MtrF membrane proteins. The structures reveal that these two transporters assemble as dimers with architectures distinct from all other families of transporters. Both YdaH and MtrF are bowl-shaped dimers with a solvent-filled basin extending from the cytoplasm halfway across the membrane bilayer. The protomers of YdaH and MtrF contain nine transmembrane helices and two hairpins. These structures directly suggest a plausible pathway for substrate transport. A combination of the crystal structure, genetic analysis and substrate accumulation assay indicates that both YdaH and MtrF behave as exporters, capable of removing the folate metabolite p-aminobenzoic acid from bacterial cells. Further experimental data based on drug susceptibility and radioactive transport assay suggest that both YdaH and MtrF participate as antibiotic efflux pumps, importantly mediating bacterial resistance to sulfonamide antimetabolite drugs. It is possible that many of these AbgT-family transporters act as exporters, thereby conferring bacterial resistance to sulfonamides. The AbgT-family transporters may be important targets for the rational design of novel antibiotics to combat bacterial infections.
Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antimetabolites; Bacteria; Bacterial Proteins; Biological Transport; Crystallography, X-Ray; Folic Acid; Gene Expression Regulation, Bacterial; Membrane Transport Proteins; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Alignment
PubMed: 26443496
DOI: 10.1002/pro.2820 -
Investigative Ophthalmology & Visual... Mar 2022The purpose of this study was to investigate the effect of antimetabolite drugs on T-cell responses and intestinal microbial composition in autoimmune uveitis.
PURPOSE
The purpose of this study was to investigate the effect of antimetabolite drugs on T-cell responses and intestinal microbial composition in autoimmune uveitis.
METHODS
Experimental autoimmune uveitis (EAU) was induced in C57BL/6J mice treated with 0.00625 mg/mL methotrexate (MTX) or 0.625 mg/mL mycophenolate mofetil (MMF) in drinking water for 4 weeks prior to immunization and 2 weeks thereafter. The effector T cell (Teff) and regulatory T cell (Treg) populations were identified using flow cytometry. The 16S rRNA gene sequencing was applied for gut microbiome characterization. DESeq2 analysis was used to discriminate relative abundances of taxa and PLS-DA to integrate cytometric and microbiome data between groups.
RESULTS
Both MTX and MMF abrogated uveitis in EAU without clinical signs of toxicity as compared to water-fed controls. MTX reduced Teff and Treg expansion in peripheral tissues and eyes. MTX decreased alpha diversity, increased Akkermansia, and reduced Lachnoclostridium abundances. Conversely, MMF enhanced Tregs in the mesenteric lymph node and the eyes. In parallel, MMF increased the gut alpha diversity, including an increased abundance of Lachnospiraceae NK4A136 group and a decreased abundance of Lachnospiraceae UCG-001. A significant congruent correlation among intestinal microbial changes, T-cell responses, and clinical scores was observed for both antimetabolites.
CONCLUSIONS
Although MTX and MMF both abrogated uveitis in EAU, they showed different effects on T-cell subsets and the intestinal bacterial composition. This work indicates unique immunomodulation by each drug and is the first to demonstrate potential microbiota-related mechanisms.
Topics: Animals; Antimetabolites; Gastrointestinal Microbiome; Immunomodulation; Mice; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Uveitis
PubMed: 35357394
DOI: 10.1167/iovs.63.3.30