Exogenous Nucleic Acids - A Potential Source of Resistance to Nucleoside Analogues in Cancer and Antiviral Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4207-4207
Author(s):  
Raymund Buhmann ◽  
Ting Yang ◽  
Martin Obermeier ◽  
Gundula Jaeger ◽  
Hans-Jochem Kolb
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Antiviral Therapy ◽  
Present Report ◽  
Nucleoside Analogues ◽  
Nucleic Acid Metabolism ◽  
Standard Drug ◽  
Polydisperse Mixture ◽  
Simplex Virus

Abstract The metabolism of exogenous nucleic acids is not well defined. Moreover, there is little information whether there might be interference with chemically and structurally related drugs, e.g. nucleoside analogues (NA) widely used in cancer or in antiviral therapy. In the present report we provide evidence, that nucleic-acid based drugs might antagonize fludarabine or acyclovir. In vitro, fludarabine treated lymphocytes or myeloid blasts where rescued from apoptosis when incubated with defibrotide (DF), a polydisperse mixture of single-stranded oligodeoxyribonucleotides (15 to 30 kD) or singular deoxynucleotides. Thereby deoxycytidine (dCTP) turned out to be the key substrate competing with fludarabine for phosphorylation by deoxycitidine kinase (dCK) and suggested interference with nucleic acid metabolism rather than direct competition with the drug. To further prove this hypothesis the influence of defibrotide on HSV replication was evaluated. In standard drug resistance assays performed with acyclovir sensitive herpes simplex virus (HSV) strains (V0631508) 4 mM of DF restored viral replication in presence of 50 mM acyclovir. This was confirmed by quantitative PCR of viral DNA. Moreover, in this case deoxythymidine (dTTP) turned out to be the competitor for intracellular phosphorylation mediated by virus thymidine kinase. We conclude that treatment with DF and other nucleic-acid-based drugs interfere with the efficacy of NA used for cancer and antiviral therapy. Prospective clinical trials are required to confirm these in vitro findings.

Therapeutic Nucleic Acids: A Potential Source of Resistance to Cancer, Antiviral and Immunosuppressive Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1614-1614 ◽  
Author(s):  
Raymund Buhmann ◽  
Ting Yang ◽  
Monica Schifferer ◽  
Martin Obermeier ◽  
Gundula Jaeger ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Antiviral Therapy ◽  
Immunosuppressive Therapy ◽  
Acid Metabolism ◽  
Nucleic Acid Metabolism ◽  
Inosine Monophosphate Dehydrogenase ◽  
Nucleotide Synthesis ◽  
Standard Drug

Abstract According to their unique structural and chemical properties nucleic acids were recognized to provide inherent therapeutic potential beyond sole information storage. In the meantime an increasing number of nucleic acid based drugs achieved FDA approval and entered clinical trails (e.g. “antisense” or “immunosustimulatory CpG” oligodeoxynucletides (ODNs), aptamers, ribozymes, RNA interference or defibrotide). But so far, no or less information is available whether these compounds might compete with chemically and structurally related drugs, e.g. nucleoside analogues (NA) widely used in cancer or antiviral therapy, or interfere with the intracellular nucleic acid metabolism. In the present report we provide evidence, that nucleic-acid based drugs antagonize fludarabine, acyclovir or mycophenolate mofetil (MMF). In presence of defibrotide (DF), a polydisperse mixture of single-stranded oligodeoxyribonucleotides (15 to 30 kD) e.g. used for treatment of hepatic veno-occlusive disease and other endothelial disorders, fludarabine treated lymphocytes or myeloid blasts where rescued from apoptosis. According to nucleic acid degradation the resulting metabolite deoxycytidine turned out to be the key substrate competing with fludarabine for phosphorylation by deoxycitidine kinase (dCK) and suggested interference with nucleic acid metabolism rather than direct competition with the drug for cellular uptake. Moreover, in standard drug resistance assays using acyclovir sensitive herpes simplex virus (HSV) strains (V0631508), 4 mM of DF restored viral replication in presence of 50 mM acyclovir. This was confirmed by quantitative PCR of viral DNA. Here, deoxythymidine turned out to be the main competitor for intracellular phosphorylation mediated by virus thymidine kinase. To further extent our findings, that an increase of the extracellular concentration of nucleic acids directly interfere with the intracellular nucleic acid metabolism, mixed lymphocyte reactions (MLRs) were performed, to test whether the immunosuppressive effects of mycophenolate mofetil (MMF) could be reversed. As control cyclosporine A (CsA) was used. Here, addition of singular ribonucleotides almost completely antagonized the T cell inhibitory effects of mycophenolic acid (MPA), respectively its prodrug MMF, but not of CsA. As MPA is known to be a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, a key enzyme for the de novo pathway of guanosine nucleotide synthesis, addition of guanosine to the MLRs was found to be effective and sufficient to reverse the immunosuppressive effects of MPA. We conclude that treatment with nucleic-acid-based drugs interfere with the intracellular nucleic acid metabolism, thus decreasing the efficacy of NAs used for cancer and antiviral therapy or the immunosuppressive therapy using MMF. Prospective clinical trials are required to confirm these in vitro findings.

scholarly journals Quantitative Evaluation of Nucleic Acid Degradability of Copper Alloy Surfaces and Its Correlation to Antibacterial Activity

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1439
Author(s):  
Akiko Yamamoto ◽  
Shinji Tanaka ◽  
Keiichiro Ohishi
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Copper Ion ◽  
Antibacterial Activities ◽  
Ion Release ◽  
Antibacterial Materials ◽  
Cu Content ◽  
Cu Alloys ◽  
Film Method

Copper (Cu) and its alloys have bactericidal activity known as “contact killing” with degradation of nucleic acids inside the bacteria, which is beneficial to inhibit horizontal gene transfer (HGF). In order to understand the nucleic acid degradability of Cu and its alloy surfaces, we developed a new in vitro method to quantitatively evaluate it by a swab method under a “dry” condition and compared it with that of commercially available antibacterial materials such as antibacterial stainless steel, pure silver, and antibacterial resins. As a result, only Cu and its alloys showed continuous degradation of nucleic acids for up to 6 h of contact time. The nucleic acid degradability levels of the Cu alloys and other antibacterial materials correlate to their antibacterial activities evaluated by a film method referring to JIS Z 2801:2012 for Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria. Nucleic acid degradation by copper (I) and (II) chlorides was confirmed at the ranges over 10 mM and 1–20 mM, respectively, suggesting that the copper ion release may be responsible for the degradation of the nucleic acids on Cu and its alloy surfaces. In conclusion, the higher Cu content in the alloys gave higher nucleic acid degradability and higher antibacterial activities.

Insulin and incorporation of radioactivity into nucleic acid fraction of isolated diaphragm

1960 ◽  
Vol 199 (4) ◽  
pp. 719-721 ◽  
Author(s):  
Ira G. Wool
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Glucose Concentration ◽  
Orotic Acid ◽  
Acid Fraction ◽  
Rat Diaphragm ◽  
Isolated Rat

Insulin in vitro stimulated the incorporation into the nucleic acid fraction of isolated rat diaphragm of radioactivity from d-glucose-U-C14, adenine-8-C14 and orotic acid-6-C14; insulin had no effect on the incorporation of thymine-2-C14 into muscle nucleic acids. Insulin enhanced the incorporation into nucleic acids of C14 from adenine and orotic acid in the absence of added glucose, and incorporation of adenine-8-C14 was not influenced by glucose concentration over the range 0–600 mg %.

scholarly journals Helicase Mechanisms During Homologous Recombination inSaccharomyces cerevisiae

2019 ◽  
Vol 48 (1) ◽  
pp. 255-273 ◽  
Author(s):  
J. Brooks Crickard ◽  
Eric C. Greene
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nucleic Acid ◽  
Homologous Recombination ◽  
Nucleic Acids ◽  
Acid Metabolism ◽  
Model Organism ◽  
Nucleic Acid Metabolism ◽  
Repair Pathway ◽  
Unidirectional Movement ◽  
Nucleoprotein Complexes

Helicases are enzymes that move, manage, and manipulate nucleic acids. They can be subdivided into six super families and are required for all aspects of nucleic acid metabolism. In general, all helicases function by converting the chemical energy stored in the bond between the gamma and beta phosphates of adenosine triphosphate into mechanical work, which results in the unidirectional movement of the helicase protein along one strand of a nucleic acid. The results of this translocation activity can range from separation of strands within duplex nucleic acids to the physical remodeling or removal of nucleoprotein complexes. In this review, we focus on describing key helicases from the model organism Saccharomyces cerevisiae that contribute to the regulation of homologous recombination, which is an essential DNA repair pathway for fixing damaged chromosomes.

Hydroxyproline-Based DNA Mimics: A Review on Synthesis and Properties

2006 ◽  
Vol 71 (7) ◽  
pp. 929-955 ◽  
Author(s):  
Vladimir A. Efimov ◽  
Oksana G. Chakhmakhcheva
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Phosphonic Acid ◽  
Peptide Nucleic Acids ◽  
Biological Properties ◽  
High Potential ◽  
Physicochemical And Biological Properties

With the aim to improve physicochemical and biological properties of natural oligonucleotides, many types of DNA analogues and mimics are designed on the basis of hydroxyproline and its derivatives, and their properties are evaluated. Among them, two types of DNA mimics representing hetero-oligomers constructed from alternating monomers of phosphono peptide nucleic acids and monomers on the base of trans-1-acetyl-4-hydroxy-L-proline (HypNA-pPNAs) and oligomers constructed from monomers containing (2S,4R)-1-acetyl-4-hydroxypyrrolidine-2-phosphonic acid backbone (pHypNAs) are of particular interest. In a set of in vitro and in vivo assays, it was shown that HypNA-pPNAs and pHypNAs demonstrated a high potential for the use in nucleic acid based diagnostics, isolation of nucleic acids and antisense experiments. A review with 53 references.

Superfamily I helicases as modular components of DNA-processing machines

2011 ◽  
Vol 39 (2) ◽  
pp. 413-423 ◽  
Author(s):  
Mark S. Dillingham
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Nucleic Acid Metabolism ◽  
Cellular Functions ◽  
Dna Helicases ◽  
Wide Range ◽  
Look Back ◽  
Partner Proteins

Helicases are a ubiquitous and abundant group of motor proteins that couple NTP binding and hydrolysis to processive unwinding of nucleic acids. By targeting this activity to a wide range of specific substrates, and by coupling it with other catalytic functionality, helicases fulfil diverse roles in virtually all aspects of nucleic acid metabolism. The present review takes a look back at our efforts to elucidate the molecular mechanisms of UvrD-like DNA helicases. Using these well-studied enzymes as examples, we also discuss how helicases are programmed by interactions with partner proteins to participate in specific cellular functions.

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