title: The antiproliferative effect of 8-chloro-adenosine, an active metabolite of 8-chloro-cyclic adenosine monophosphate, and disturbances in nucleic acid synthesis and cell cycle kinetics.
abstract: 8-Chloro-adenosine, the dephosphorylated metabolite of the antineoplastic agent 8-chloro-cyclic AMP, has been proposed to act on the regulatory subunits of cyclic AMP-dependent protein kinase. 8-Chloro-adenosine has a growth-inhibitory effect, the mechanism of which is unclear. We investigated the effects of 8-chloro-cyclic AMP and 8-chloro-adenosine on nucleic acid synthesis and cell cycle kinetics in two human glioma cell lines. These effects were compared to those of the cyclic AMP analogue 8-(4-chlorophenyl)-thio-cyclic AMP (8-CPTcAMP), which is less susceptible to dephosphorylation. Whereas 8-CPTcAMP almost completely inhibited RNA and DNA synthesis, both 8-chloro-adenosine and 8-chloro-cyclic AMP only partly inhibited synthesis of RNA and DNA at growth-inhibitory concentrations, as demonstrated by using [5-1H] uridine and [14C]thymidine incorporation. Therefore, the growth-inhibitory effect of 8-chloro-cyclic AMP is not (or not completely) due to activation of cyclic AMP-dependent protein kinase nor to the inhibition of nucleic acid synthesis. Flow cytometric analysis revealed that 8-chloro-cyclic AMP and 8-chloro-adenosine probably block cell cycle progression at the G2M phase. The effects of 8-chloro-cyclic AMP on nucleic acid synthesis and cell cycle progression were largely prevented by adenosine deaminase, which inactivates 8-chloro-adenosine. This indicates that the effects of 8-chloro-cyclic AMP were at least in part due to its metabolite 8-chloro-adenosine. Incorporation of 8-chloro-adenosine into RNA and DNA might contribute to the disturbance of the cell cycle kinetics and growth-inhibitory effect of 8-chloro-adenosine.
authors.affiliation: Department of Neurology, Graduate School of Neurosciences Amsterdam, Vrije Universiteit, The Netherlands.
authors.forename: C H
authors.initials: CH
authors.lastname: Langeveld
authors.forename: C A
authors.initials: CA
authors.lastname: Jongenelen
authors.forename: J W
authors.initials: JW
authors.lastname: Theeuwes
authors.forename: J P
authors.initials: JP
authors.lastname: Baak
authors.forename: J J
authors.initials: JJ
authors.lastname: Heimans
authors.forename: J C
authors.initials: JC
authors.lastname: Stoof
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D005434:Flow Cytometry; D006801:Humans; D012313:RNA / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D012313:RNA; D004247:DNA; C044258:8-chloro-cyclic adenosine monophosphate; C075440:8-chloroadenosine