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Relationship between Intracellular Concentration of S-Adenosylhomocysteine and Inhibition of Vaccinia Virus Replication and Inhibition of Murine L-929 Cell Growth
dc.contributor.author | Hasobe, Masahide | |
dc.contributor.author | McKee, James G. | |
dc.contributor.author | Borchardt, Ronald T. | |
dc.date.accessioned | 2015-05-08T15:39:40Z | |
dc.date.available | 2015-05-08T15:39:40Z | |
dc.date.issued | 1989-06 | |
dc.identifier.citation | Haasobe, Masahide, James G. McKee, and Ronald T. Borchardt. "Relationship between Intracellular Concentration of S-Adenosylhomocysteine and Inhibition of Vaccinia Virus Replication and Inhibition of Murine L-929 Cell Growth." Antimicrob. Agents Chemother. June 1989 vol. 33 no. 6 828-834.http://dx.doi.org/10.1128/AAC.33.6.828 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/17658 | |
dc.description.abstract | 9-(trans-2',trans-3'-Dihydroxycyclopent-4'-enyl)-adenine (compound 1) and -3-deazaadenine (compound 2), which are specific inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were reported earlier by our laboratory (M. Hasobe, J. G. McKee, D. R. Borcherding, and R. T. Borchardt, Antimicrob. Agents Chemother. 31:1849-1851, 1987) to have anti-vaccinia virus activity with reduced murine L-929 cell toxicity compared with the prototype compound neplanocin A. In this study, we showed that the antiviral and cytotoxic effects of compounds 1 and 2 can be related to intracellular concentrations of AdoHey, which are elevated in cells treated with these inhibitors of AdoHcy hydrolase. For example, concentrations of analogs 1 and 2 that produce 50% inhibition of vaccinia virus replication caused only slight elevations in intracellular levels of AdoHcy (from 50 [controls] to 100 to 125 [drug-treated cells] pmol/mg of protein) and elevations in the ratios of AdoHcy/S-adenosylmethionine (from 0.05 to 0.1 [controls] to 0.15 to 0.19 [drug-treated cells]). In contrast to the extreme susceptibility of virus replication to slight elevations in intracellular AdoHcy, cell viability was quite tolerant to higher levels of this metabolite. For example, concentrations of analogs 1 and 2 that produced 50% inhibition of L-929 cell replication caused significant increases in intracellular levels of AdoHcy (to 825 to 950 pmol/mg of protein) and elevations in AdoHcy/S-adenosylmethionine ratios (approximately 1.3). These data make it possible to assign a therapeutic index of 7 to 8 to these compounds on the basis of the comparison of intracellular levels of AdoHcy that caused 50% inhibition of vaccinia virus replication with those that caused 50% inhibition of L-929 cell replication. | en_US |
dc.description.sponsorship | This work was supported by a Public Health Service grant from the National Institutes of Health (GM-29332) and a grant from Glaxo, Inc. | en_US |
dc.publisher | The American Society for Microbiology | en_US |
dc.title | Relationship between Intracellular Concentration of S-Adenosylhomocysteine and Inhibition of Vaccinia Virus Replication and Inhibition of Murine L-929 Cell Growth | en_US |
dc.type | Article | |
kusw.kuauthor | Hasobe, Mashide | |
kusw.kuauthor | McKee, James G. | |
kusw.kuauthor | Borchardt, Ronald T. | |
kusw.kudepartment | Department of Pharmaceutical Chemisty | en_US |
dc.identifier.doi | 10.1128/AAC.33.6.828 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item does not meet KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |