A PROPOSED MECHANISM FOR THE ACTION OF 9-β-<scp>D</scp>-ARABINO-FURANOSYLADENINE AS AN INHIBITOR OF THE GROWTH OF SOME ASCITES CELLS

York, James L.; LePage, G. A.

doi:10.1139/o66-003

Cited by 80 publications

(21 citation statements)

References 10 publications

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“…two kinds of anti-deoxyribonucleic acid replicaIt is interesting to speculate about the mecha-tive activity: (i) ara-nucleotide inhibition of ribonucleotide reductase (16,21) and (ii) aranucleotide inhibition of deoxyribonucleic acid polymerase (9). Ara-A is known not to inhibit ribonucleic acid polymerase and to be incorporated into new cellular nucleic acid at a rate of 0.2% or less (5).…”

Section: Resultsmentioning

confidence: 99%

Effect of Adenosine Deaminase upon the Antiviral Activity In Vitro of Adenine Arabinoside for Vaccinia Virus

Connor

Sweetman

Carey

et al. 1974

Antimicrob Agents Chemother

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This study determined that the effect of 9-fl-D-arabinofuranosyl-adenine (adenine arabinoside, Ara-A) upon vaccinia virus plaque developmeAt in the stable monkey kidney line, LLC-MK2, was increased approximately 40-fold when an inhibitor of adenosine deaminase (ADA) was added to the tissue culture media along with infective inocula. The concentration of Ara-A required to completely suppress plaqtet development (total plaque inhibitory concentra. tion,0 ; TPIC OO) was greater than 10 ,g/ml, However, when ADA activity was inhibited, the TPIC,O0 was 0.5 gg/ml or less. Chromatographic assay of arabinosylpurines in the media provided evidence that adenine arabinoside was rapidly deaminated to 9-#-D-arabihefuranosy!hypoxanthine by the cellular monolayers, in the absence of animal serum, and that the rate of deamination, at 5 #g/ml, by the cells was equal to the rate of diffusion of Ara-A across the cellular iiiembrane. The half-life of Ara-A in the media, startnhg with 5 ,ug/ml, was 2 to 3 h and shorter at lower concentrations. The study demonstrates the profound effect that an indicator system, acting as an intact biological unit, can have upon a potential antiviral compound.-

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Section: Resultsmentioning

confidence: 99%

Effect of Adenosine Deaminase upon the Antiviral Activity In Vitro of Adenine Arabinoside for Vaccinia Virus

Connor

Sweetman

Carey

et al. 1974

Antimicrob Agents Chemother

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“…When used at the highest concentration of ara-A tested (600 uM), hydroxyurea did not produce a selective inhibition of linear DNA. The maximum selective effect (at any concentration of hydroxyurea tested) was an (16,18,19), and three mechanisms have been proposed for the inhibition of DNA synthesis based on the action of ara-ATP (the 5'-triphosphate of ara-A) (20): (i) the fraudulent nucleotide may be incorporated into DNA and function as a chain terminator (21); (ii) ribonucleoside diphosphate reductase might be inhibited by ara-ATP, thereby depriving the cell of deoxynucleoside triphosphates (22,23); and (iii) the synthesis of DNA may be inhibited directly by the action of ara-ATP on DNA polymerase (20,22).…”

Section: -F3-d-arabinofuranosylmentioning

confidence: 99%

“…DNA was labeled with tritium by replacing the medium of early-log-phase cells with a medium containing 10 uCi of [3H]thymidine/ml (6.7 Ci/mmol). After 22 hr the radioactive medium was removed. The cells were washed twice and incubated with fresh medium for 1 hr to exhaust the intracellular pool of radioactive thymidine and thymidine phosphates (10).…”

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confidence: 99%

Selective Inhibition of Nuclear DNA Synthesis by 9-β-D-Arabinofuranosyl Adenine in Rat Cells Transformed by Rous Sarcoma Virus

Shipman

Smith

Drach

1972

Proc. Natl. Acad. Sci. U.S.A.

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The drug, 9-,6-D-arabinofuranosyl adenine, selectively inhibits the synthesis of nuclear DNA without affecting extrachromosomal DNA synthesis in rat cells transformed by Rous sarcoma virus (B-mix K-44/6 To explore the role of extrachromosomal DNA in virustransformed cells, we have begun to examine circular DNA from a line of mammalian cells transformed by Rous sarcoma virus (RSV). B-mix K44/6 cells were subcloned from a population of embryonic rat cells transformed in vitro by the Prague strain of RSV (1). These large epithelioid cells are malignant for homologous rat hosts and have been shown by both in vivo experiments (1) and cell fusion studies with chick-embryo fibroblasts (Shipman, unpublished observations) to contain the genome of RSV. Circular DNA represents a very small fraction of the total DNA of a mammalian cell. Therefore, to aid in the isolation of circular DNA it would be desirable to inhibit nuclear DNA synthesis without affecting the replication of circular DNA. A selective inhibition of this nature has been accomplished in prokaryotic cells. Helinski and Clewell (2) have described a preparation using chloramphenicol, where Col E1 plasmid DNA synthesis occurs in the absence of chromosomal DNA synthesis. Similarly, in synchronous cultures of Chlorella, synthesis of nuclear DNA was inhibited by more than 90% in the presence of 15 ,pM cycloheximide, whereas the inhibitor had little effect on satellite DNA synthesis (3). Although the synthesis of cytoplasmic DNA in HeLa cells is somewhat resistant to inhibition by high concentrations of hydroxyurea (4), the selective inhibition of nuclear DNA synthesis has not been described in mammalian cells.Abbreviations: ara-A, 9-0-D-arabinofuranosyl adenine; ara-ATP, the 5'-triphosphate of ara-A; Col El, colicinogenic factor E1; HBS, HEPES-buffered saline (see ref. 12); HEPES, 4-(2-hydroxyethyl)-l-piperazine-ethanesulfonic acid; PI, propidium diiodide; RSV, Rous sarcoma virus; SDS, sodium dodecyl sulfate.

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“…AlT was first prepared by HOrwitz(1964)and displays promising anti-AIDS activity in initial clinical trials (yarchoan, 1986).Along with ddCyd, and the other nucleoside analogues; AlT acts following metabolic conversion to its 5' -triphosphate (Furman, 1986;Cooney, 1986). This may lead to the problem, common among nucleoside analogues, of a poor clinical response resulting from poor cellular phosphorylation (york, 1966;Furman, 1979). Furthermore, amino-nucleosides, such as ddCyd, are subject to metabolic deamination, a conversion which often brings a diminution of biological activity (Bryson, 1976;Haskell, 1977).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

McGuigan

Nicholls

O’Connor

et al. 1990

Antivir Chem Chemother

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SummaryThe reaction of thymidine with diethyl, dipropyl, and dibutyl phosphorochloridates yields novel 5/-(dialkyl phosphates), characterized by spectroscopic and analytical data. These are readily mesylated at the 3'-position. Similar reaction of 3'-0-acetyl and 3'-0-ethyl thymidine with dialkyl phosphorochloridates gives an analogous series of compounds. Lastly, reaction of the anti-AIDS drug AZT with these phosphorylating agents gives the corresponding 3'-azido products. It was hoped that these might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT and that the alternative 3/ -substituents might also confer similar activity. In fact, none of the compounds studied displayed any anti-HIV activity in vitro. This is attributed to the metabolic stability of the trialkyl phosphate moiety.

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A PROPOSED MECHANISM FOR THE ACTION OF 9-β-D-ARABINO-FURANOSYLADENINE AS AN INHIBITOR OF THE GROWTH OF SOME ASCITES CELLS

Cited by 80 publications

References 10 publications

Effect of Adenosine Deaminase upon the Antiviral Activity In Vitro of Adenine Arabinoside for Vaccinia Virus

Effect of Adenosine Deaminase upon the Antiviral Activity In Vitro of Adenine Arabinoside for Vaccinia Virus

Selective Inhibition of Nuclear DNA Synthesis by 9-β-D-Arabinofuranosyl Adenine in Rat Cells Transformed by Rous Sarcoma Virus

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

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