Cancer Science Standard Abbreviations List
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Deoxyguanosine Cytotoxicity by a Novel Inhibitor of Furine Nucleoside Phosphorylase, 8-Amino-9-Benzylguanine1
[CANCER RESEARCH 46, 519-523, February 1986] Potentiation of 2'-Deoxyguanosine Cytotoxicity by a Novel Inhibitor of Furine Nucleoside Phosphorylase, 8-Amino-9-benzylguanine1 Donna S. Shewach,2 Ji-Wang Chern, Katherine E. Pillóte,Leroy B. Townsend, and Peter E. Daddona3 Departments of Internal Medicine [D.S.S., P.E.D.], Biological Chemistry [P.E.D.], and Medicinal Chemistry [J-W.C., K.E.P., L.B.T.], University ol Michigan, Ann Arbor, Michigan 48109 ABSTRACT to the ADA-deficient disease state (2). PNP is an essential enzyme of the purine salvage pathway, We have synthesized and evaluated a series of 9-substituted catalyzing the phosphorolysis of guanosine, inosine, and their analogues of 8-aminoguanine, a known inhibitor of human purine 2'-deoxyribonucleoside derivatives to the respective purine nucleoside phosphorylase (PNP) activity. The ability of these bases. To date, several inhibitors of PNP have been identified, agents to inhibit PNP has been investigated. All compounds were and most of these compounds resemble purine bases or nucleo found to act as competitive (with inosine) inhibitors of PNP, with sides. The most potent inhibitors exhibit apparent K¡values in K¡values ranging from 0.2 to 290 /¿M.Themost potent of these the range of 10~6to 10~7 M (9-12). Using partially purified human analogues, 8-amino-9-benzylguanine, exhibited a K, value that erythrocyte PNP, the diphosphate derivative of acyclovir dis was 4-fold lower than that determined for the parent base, 8- played K¡values of 5.1 x 10~7 to 8.7 x 10~9 M, depending on aminoguanine. -
List of Abbreviations
List of Abbreviations 1,3BPGA 1,3-Bisphospho-D-glycerate 10-formyl THF 10-Formyltetrahydrofolate 2PG 2-phospho-D-glycerate 3PG 3-phospho-D-glycerate 3PPyr 3-phosphonooxypyruvate 3PSer 3-phosphoserine 6PDG 6-phospho-D-gluconate 6Pgl glucono-1,5-lactone-6-phosphate AcAcACP acetoacetyl-ACP AcAcCoA acetoacetyl-CoA AcACP acetyl-ACP AcCoA acetyl-CoA ACP acyl carrier protein ADP adenosine 5'-diphosphate AKG alpha-ketoglutarate Ala alanine AMP adenosine 5'-monophosphate Arg arginine ArgSuc argininosuccinate Asn asparagine Asp aspartate ATP adenosine 5'-triphosphate CDP cytidine 5'-diphosphate Chol cholesterol Ci citrulline Cit citrate CMP cytidine 5'-monophosphate CO2 carbon dioxide CoA coenzyme A CP carbamoyl-phosphate CTP cytidine 5'-triphosphate Cytc-ox ferricytochrome c Cytc-red ferrocytochrome c dADP 2'-deoxyadenosine 5'-diphosphate dAMP 2'-deoxyadenosine 5'-monophosphate dCDP 2'-deoxycytosine 5'-diphosphate dCMP 2'-deoxycytosine 5'-monophosphate dGDP 2'-deoxyguanosine 5'-diphosphate dGMP 2'-deoxyguanosine 5'-monophosphate DHAP dihydroxyacetone phosphate DHF 7,8-Dihydrofolate dTMP 2'-Deoxythymidine-5'-monophosphate dUDP 2'-Deoxyuridine-5'-diphosphate dUMP 2'-Deoxyuridine-5'-monophosphate Ery4P erythrose-4-phosphate F16BP fructose 1,6-bisphosphate F6P fructose 6-phosphate FAD flavin adenine dinucleotide FADH2 flavin adenine dinucleotide reduced for formate fPP farnesyl diphosphate Fum fumarate G6P glucose 6-phosphate GA guanidinoacetate GA3P glyceraldehyde 3-phosphate GDP guanosine 5'-diphosphate Glc glucose Gln glutamine Glu glutamate GluSA -
2'-Deoxyguanosine Toxicity for B and Mature T Lymphoid Cell Lines Is Mediated by Guanine Ribonucleotide Accumulation
2'-deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation. Y Sidi, B S Mitchell J Clin Invest. 1984;74(5):1640-1648. https://doi.org/10.1172/JCI111580. Research Article Inherited deficiency of the enzyme purine nucleoside phosphorylase (PNP) results in selective and severe T lymphocyte depletion which is mediated by its substrate, 2'-deoxyguanosine. This observation provides a rationale for the use of PNP inhibitors as selective T cell immunosuppressive agents. We have studied the relative effects of the PNP inhibitor 8- aminoguanosine on the metabolism and growth of lymphoid cell lines of T and B cell origin. We have found that 2'- deoxyguanosine toxicity for T lymphoblasts is markedly potentiated by 8-aminoguanosine and is mediated by the accumulation of deoxyguanosine triphosphate. In contrast, the growth of T4+ mature T cell lines and B lymphoblast cell lines is inhibited by somewhat higher concentrations of 2'-deoxyguanosine (ID50 20 and 18 microM, respectively) in the presence of 8-aminoguanosine without an increase in deoxyguanosine triphosphate levels. Cytotoxicity correlates instead with a three- to fivefold increase in guanosine triphosphate (GTP) levels after 24 h. Accumulation of GTP and growth inhibition also result from exposure to guanosine, but not to guanine at equimolar concentrations. B lymphoblasts which are deficient in the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase are completely resistant to 2'-deoxyguanosine or guanosine concentrations up to 800 microM and do not demonstrate an increase in GTP levels. Growth inhibition and GTP accumulation are prevented by hypoxanthine or adenine, but not by 2'-deoxycytidine. -
Triphosphate Accumulation, DNA Damage, and Growth Inhibition Following Exposure to CB3717 and Dipyridamole Nicola J
(CANCER RESEARCH 51. 2346-2352, May I. 1991) Mechanism of Cell Death following Thymidylate Synthase Inhibition: 2'-Deoxyuridine-5'-triphosphate Accumulation, DNA Damage, and Growth Inhibition following Exposure to CB3717 and Dipyridamole Nicola J. Curtin,1 Adrian L. Harris, and G. Wynne Aherne Cancer Research L'nil, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne [N. J. C.J; Imperial Cancer Research Fund Clinical Oncology Unit, Churchill Hospital, Headington, Oxon ¡A.L. H.]; Department of Biochemistry, University of Surrey, Guildford, Surrey [G. W. A.], England ABSTRACT but one hypothesis, based on the study of bacterial mutants (3- The thymidylate synthasc inhibitor /V'°-propargyl-5,8-dideazafolic 5), is that TS inhibition leads not only to a reduction in dTTP levels but also, as dUMP accumulates behind the block, to the acid (CB3717) inhibits the growth of human lung carcinoma A549 cells. formation of dUTP. The levels of dUTP eventually overwhelm The cytotoxicity of CB3717 is potentiated by the nucleoside transport inhibitor dipyridamole (DP), which not only inhibits the uptake and dUTPase (the enzyme which breaks down dUTP to dUMP) therefore salvage of thymidine but also inhibits the efflux of deoxyuridine, and the levels of dUTP increase. DNA polymerase can utilize thereby enhancing the intracellular accumulation of deoxyuridine nucleo- dUTP and dTTP with equal efficiency (6), such that uracil is tides. Measurement of intracellular deoxyuridine triphosphate (dUTP) misincorporated into DNA. Uracil in DNA is excised rapidly pools, by sensitive radioimmunoassay, demonstrated a large increase in by uracil glycosylase, leaving an apyrimidinic site. During repair response to CB3717, in a dose- and time-related manner, and this of apyrimidinic sites, in the presence of unbalanced dUTP/ accumulation was enhanced by coincubation with DP. -
Central Nervous System Dysfunction and Erythrocyte Guanosine Triphosphate Depletion in Purine Nucleoside Phosphorylase Deficiency
Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from Archives of Disease in Childhood, 1987, 62, 385-391 Central nervous system dysfunction and erythrocyte guanosine triphosphate depletion in purine nucleoside phosphorylase deficiency H A SIMMONDS, L D FAIRBANKS, G S MORRIS, G MORGAN, A R WATSON, P TIMMS, AND B SINGH Purine Laboratory, Guy's Hospital, London, Department of Immunology, Institute of Child Health, London, Department of Paediatrics, City Hospital, Nottingham, Department of Paediatrics and Chemical Pathology, National Guard King Khalid Hospital, Jeddah, Saudi Arabia SUMMARY Developmental retardation was a prominent clinical feature in six infants from three kindreds deficient in the enzyme purine nucleoside phosphorylase (PNP) and was present before development of T cell immunodeficiency. Guanosine triphosphate (GTP) depletion was noted in the erythrocytes of all surviving homozygotes and was of equivalent magnitude to that found in the Lesch-Nyhan syndrome (complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency). The similarity between the neurological complications in both disorders that the two major clinical consequences of complete PNP deficiency have differing indicates copyright. aetiologies: (1) neurological effects resulting from deficiency of the PNP enzyme products, which are the substrates for HGPRT, leading to functional deficiency of this enzyme. (2) immunodeficiency caused by accumulation of the PNP enzyme substrates, one of which, deoxyguanosine, is toxic to T cells. These studies show the need to consider PNP deficiency (suggested by the finding of hypouricaemia) in patients with neurological dysfunction, as well as in T cell immunodeficiency. http://adc.bmj.com/ They suggest an important role for GTP in normal central nervous system function. -
Cyclic Adenosine 3':5'-Monophc;Phate and Cyclic Guanosine 3':5'
1 CYCLIC ADENOSINE 3':5'-MONOPHC;PHATE AND CYCLIC GUANOSINE 3':5'- MONOPHOSPHATE METABOLISM DURING THE MITOTIC CYCLE OF THE ACELLULAR SLIME MOULD PHYSABUM POLYCEPHALUM ( SCHWEINITZ ) by James Richard Lovely B.Sc. A.R.C.S. Submitted in part fulfilment for the degree of Doctor of Philosophy of the University of London. September 1977 Department of Botany, Imperial College, London SW7 2AZ. ABSTRACT. Several methods have been assessed and the most effective used for the extraction, purification, separation and assay of cyclic AMP and cyclic GMP from the acellular slime mould Physarum polycephalum. Both cyclic nucleotides have been measured at half hourly intervals in synchronous macroplasmodia. Cyclic AMP was maximal in the last quarter of G2 while cyclic GMP showed two maxima, one occurring during S phase and the other late in G2. Enzymes synthesising and degrading these cyclic nucleotides and their sensitivity to certain inhibitors and cations have been assayed by new radiometric methods in which the tritium labelled substrate and product are separated by thin layer chromatography on cellulose. Synchronous surface plasmodia have been homogenised and sepa- rated into three fractions by differential centrifugation. Phosphodiesterase activity of each fraction has been measured using tritium labelled cyclic AMP and cyclic GMP as substrate. During the 8 hour mitotic cycle, no significant change of either enzyme in any fraction was detected. Adenylate and guanylate cyclase activity has been measured using the tritium labelled imidophosphate analogues as substrate. Adenylate cyclase activity in a low speed particulate fraction increased by about 50% in late G2. No significant changes were detected at any time in the high speed particulate or soluble fractions. -
Oxidative Stress and the Guanosine Nucleotide Triphosphate Pool: Implications for a Biomarker and Mechanism of Impaired Cell Function
University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2008 OXIDATIVE STRESS AND THE GUANOSINE NUCLEOTIDE TRIPHOSPHATE POOL: IMPLICATIONS FOR A BIOMARKER AND MECHANISM OF IMPAIRED CELL FUNCTION Celeste Maree Bolin The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Bolin, Celeste Maree, "OXIDATIVE STRESS AND THE GUANOSINE NUCLEOTIDE TRIPHOSPHATE POOL: IMPLICATIONS FOR A BIOMARKER AND MECHANISM OF IMPAIRED CELL FUNCTION" (2008). Graduate Student Theses, Dissertations, & Professional Papers. 728. https://scholarworks.umt.edu/etd/728 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. OXIDATIVE STRESS AND THE GUANOSINE NUCLEOTIDE TRIPHOSPHATE POOL: IMPLICATIONS FOR A BIOMARKER AND MECHANISM OF IMPAIRED CELL FUNCTION By Celeste Maree Bolin B.A. Chemistry, Whitman College, Walla Walla, WA 2001 Dissertation presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Toxicology The University of Montana Missoula, Montana Spring 2008 Approved by: Dr. David A. Strobel, Dean Graduate School Dr. Fernando Cardozo-Pelaez, -
Distribution of Nucleosides in Populations of Cordyceps Cicadae
Molecules 2014, 19, 6123-6141; doi:10.3390/molecules19056123 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Distribution of Nucleosides in Populations of Cordyceps cicadae Wen-Bo Zeng 1, Hong Yu 1,*, Feng Ge 2, Jun-Yuan Yang 1, Zi-Hong Chen 1, Yuan-Bing Wang 1, Yong-Dong Dai 1 and Alison Adams 3 1 Yunnan Herbal Laboratory, Institute of Herb Biotic Resources, Yunnan University, Kunming 650091, Yunnan, China; E-Mails: [email protected] (W.-B.Z.); [email protected] (J.-Y.Y.); [email protected] (Z.-H.C.); [email protected] (Y.-B.W.); [email protected] (Y.-D.D.) 2 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China; E-Mail: [email protected] 3 Department of Biological Sciences, College of Engineering, Forestry and Natural Science, Northern Arizona University, Flagstaff, AZ 86011-5640, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected] or [email protected]; Tel.: +86-137-006-766-33; Fax: +86-871-650-346-55. Received: 15 January 2014; in revised form: 25 April 2014 / Accepted: 5 May 2014 / Published: 14 May 2014 Abstract: A rapid HPLC method had been developed and used for the simultaneous determination of 10 nucleosides (uracil, uridine, 2'-deoxyuridine, inosine, guanosine, thymidine, adenine, adenosine, 2'-deoxyadenosine and cordycepin) in 10 populations of Cordyceps cicadae, in order to compare four populations of Ophicordyceps sinensis and one population of Cordyceps militaris. Statistical analysis system (SAS) 8.1 was used to analyze the nucleoside data. -
Deoxyadenosine Triphosphate As a Mediator of Deoxyguanosine Toxicity in Cultured T Lymphoblasts
Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts. G J Mann, R M Fox J Clin Invest. 1986;78(5):1261-1269. https://doi.org/10.1172/JCI112710. Research Article The mechanism by which 2'-deoxyguanosine is toxic for lymphoid cells is relevant both to the severe cellular immune defect of inherited purine nucleoside phosphorylase (PNP) deficiency and to attempts to exploit PNP inhibitors therapeutically. We have studied the cell cycle and biochemical effects of 2'-deoxyguanosine in human lymphoblasts using the PNP inhibitor 8-aminoguanosine. We show that cytostatic 2'-deoxyguanosine concentrations cause G1-phase arrest in PNP-inhibited T lymphoblasts, regardless of their hypoxanthine guanine phosphoribosyltransferase status. This effect is identical to that produced by 2'-deoxyadenosine in adenosine deaminase-inhibited T cells. 2'-Deoxyguanosine elevates both the 2'-deoxyguanosine-5'-triphosphate (dGTP) and 2'-deoxyadenosine-5'-triphosphate (dATP) pools; subsequently pyrimidine deoxyribonucleotide pools are depleted. The time course of these biochemical changes indicates that the onset of G1-phase arrest is related to increase of the dATP rather than the dGTP pool. When dGTP elevation is dissociated from dATP elevation by coincubation with 2'-deoxycytidine, dGTP does not by itself interrupt transit from the G1 to the S phase. It is proposed that dATP can mediate both 2'-deoxyguanosine and 2'-deoxyadenosine toxicity in T lymphoblasts. Find the latest version: https://jci.me/112710/pdf Deoxyadenosine Triphosphate as a Mediator of Deoxyguanosine Toxicity in Cultured T Lymphoblasts G. J. Mann and R. M. Fox Ludwig Institute for Cancer Research (Sydney Branch), University ofSydney, Sydney, New South Wales 2006, Australia Abstract urine of PNP-deficient individuals, with elevation of plasma inosine and guanosine and mild hypouricemia (3). -
CFA As a Clinically Translatable Probe for PET Imaging of Deoxycytidine Kinase Activity
[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity Woosuk Kima,b,1, Thuc M. Lea,b,1, Liu Weia,b, Soumya Poddara,b, Jimmy Bazzya,b, Xuemeng Wanga,b, Nhu T. Uonga,b, Evan R. Abta,b, Joseph R. Capria,b, Wayne R. Austinc, Juno S. Van Valkenburghb,d, Dalton Steeleb,d, Raymond M. Gipsond, Roger Slavika,b, Anthony E. Cabebea,b, Thotsophon Taechariyakula,b, Shahriar S. Yaghoubie, Jason T. Leea,f, Saman Sadeghia,b, Arnon Lavieg, Kym F. Faulla,b,h,i, Owen N. Wittea,j,k,l, Timothy R. Donahuea,b,m, Michael E. Phelpsa,f,2, Harvey R. Herschmana,b,n, Ken Herrmanna,b, Johannes Czernina,b, and Caius G. Radua,b,2 aDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; bAhmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; cAbcam, Cambridge, MA 02139-1517; dDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; eCellSight Technologies, Inc., San Francisco, CA 94107; fCrump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095; gDepartment of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607; hThe Pasarow Mass Spectrometry Laboratory, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095; iDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095; jDepartment of Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, CA 90095; kHoward Hughes Medical Institute, University of California, Los Angeles, CA 90095; lEli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; mDepartment of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and nDepartment of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 Contributed by Michael E. -
Developmental Disorder Associated with Increased Cellular Nucleotidase Activity (Purine-Pyrimidine Metabolism͞uridine͞brain Diseases)
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 11601–11606, October 1997 Medical Sciences Developmental disorder associated with increased cellular nucleotidase activity (purine-pyrimidine metabolismyuridineybrain diseases) THEODORE PAGE*†,ALICE YU‡,JOHN FONTANESI‡, AND WILLIAM L. NYHAN‡ Departments of *Neurosciences and ‡Pediatrics, University of California at San Diego, La Jolla, CA 92093 Communicated by J. Edwin Seegmiller, University of California at San Diego, La Jolla, CA, August 7, 1997 (received for review June 26, 1997) ABSTRACT Four unrelated patients are described with a represent defects of purine metabolism, although no specific syndrome that included developmental delay, seizures, ataxia, enzyme abnormality has been identified in these cases (6). In recurrent infections, severe language deficit, and an unusual none of these disorders has it been possible to delineate the behavioral phenotype characterized by hyperactivity, short mechanism through which the enzyme deficiency produces the attention span, and poor social interaction. These manifesta- neurological or behavioral abnormalities. Therapeutic strate- tions appeared within the first few years of life. Each patient gies designed to treat the behavioral and neurological abnor- displayed abnormalities on EEG. No unusual metabolites were malities of these disorders by replacing the supposed deficient found in plasma or urine, and metabolic testing was normal metabolites have not been successful in any case. except for persistent hypouricosuria. Investigation of purine This report describes four unrelated patients in whom and pyrimidine metabolism in cultured fibroblasts derived developmental delay, seizures, ataxia, recurrent infections, from these patients showed normal incorporation of purine speech deficit, and an unusual behavioral phenotype were bases into nucleotides but decreased incorporation of uridine. -
N2 Atom of Guanine and N6 Atom of Adenine Residues As Sites for Covalent Binding of Metabolically Activated 1'-Hydroxysafrole to Mouse Liver DMA in V/Vo1
[CANCER RESEARCH 41, 2664-2671, July 1981] 0008-5472/81 /0041-OOOOS02.00 N2 Atom of Guanine and N6 Atom of Adenine Residues as Sites for Covalent Binding of Metabolically Activated 1'-Hydroxysafrole to Mouse Liver DMA in V/vo1 David H. Phillips,2 James A. Miller,3 Elizabeth C. Miller, and Bruce Adams McArdle Laboratory for Cancer Research [D. H. P., J. A. M., E. C. M.¡and Department of Chemistry ¡B.A.], University of Wisconsin, Madison. Wisconsin 53706 ABSTRACT use of safrole and sassafras oil (containing safrole) as food Administration of 1'-[2',3'-3H]hydroxysafrole to adult female additives was banned in the United States in 1960, safrole continues to be ingested in small amounts by humans since it mice resulted in the formation of DMA-, ribosomal RNA-, and is a minor component of a number of other essential oils and of protein-bound adducts in the liver that reached maximum levels some herbs and spices, including anise, basil, nutmeg, mace, within 24 hr. The levels of all three macromolecule-bound and pepper (12, 13, 20). adducts decreased rapidly between 1 and 3 days after injec Current evidence (reviewed in Refs. 22 and 27) suggests tion, at which time the amounts of the DMA-bound adducts that a property common to most chemical carcinogens is that essentially plateaued at approximately 15% of the maximum their biologically active forms are electrophilic. The majority of level. The amounts of the protein and ribosomal RNA adducts carcinogens are not electrophilic as such and must undergo were very low by 20 days.