Inhibition of HSV-transformed murine cells by nucleoside analogs, 2'-NDG and 2'-nor-cGMP: mechanisms of inhibition and reversal by exogenous nucleosides.
A murine cell line transformed with HSV TK (LH-1) exhibits a greatly enhanced cytotoxicity to the nucleoside analog 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy) methyl]guanine (2'-NDG) as compared to the parental LM cell line (I50 LH-1 = 0.4 microM; I50 LM = 44.4 microM). Toxicity of 2'-NDG for LH-1 and LM is reversed only by the addition of 100 microM thymidine (dThd), indicating that 2'-NDG is a substrate for the viral and cellular TK. In LM(TK-) cells--murine cells expressing no TK activity, 2'-NDG cytotoxicity is partially reversed only with dGuo. A cyclic phosphate derivative of 2'-NDG, 2'-nor-cGMP, contains a phosphodiester bond, is also taken up by cells, and does not depend on viral TK for activation. LH-1 cells and LM(TK-) cells are inhibited by similar concentrations of this analog (5.1 and 4.1 microM, respectively). In all three cell lines (LM, LH-1, LM(TK-], the toxicity of 2'-nor-cGMP is significantly reversed with dGuo or cyclic dGMP. This pattern of reversal differs significantly from that observed with 2'-NDG, suggesting that 2'-nor-cGMP is metabolized as a guanosine analog, similar to acyclovir, in LM and LM(TK-) cells. These results indicate that a cyclic monophosphate analog of 2'-NDG can be activated independently of viral TK expression and that cellular metabolic pathways resulting in elevated dGTP concentrations are important for reversal of toxicity induced by guanosine-like nucleoside analogs.
Oliver
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Bubley
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Crumpacker
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D000212:Acyclovir / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003841:Deoxycytidine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000494:pharmacology; D015774:Ganciclovir; D006147:Guanine / Q000031:analogs & derivatives*; D051379:Mice; D009943:Organophosphorus Compounds; D018139:Simplexvirus / Q000502:physiology*; D013936:Thymidine / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism
D009943:Organophosphorus Compounds; D003841:Deoxycytidine; D006147:Guanine; C045511:9-((2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl)guanine P-oxide; D013937:Thymidine Kinase; D003849:Deoxyguanosine; D006152:Cyclic GMP; D015774:Ganciclovir; D013936:Thymidine; D000212:Acyclovir