Relationship between intracellular concentration of S-adenosylhomocysteine and inhibition of vaccinia virus replication and inhibition of murine L-929 cell growth.
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.
Hasobe
M
M
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
McKee
J G
JG
Borchardt
R T
RT
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006710:Homocysteine / Q000031:analogs & derivatives*; D006867:Hydrolases / Q000378:metabolism; D007739:L Cells; D008745:Methylation; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D014616:Vaccinia virus / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D006710:Homocysteine; C031096:neplanocin A; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine