title: Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors.
abstract: Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A(1), A(2A), or A(3) receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A(2B) receptors. Clofarabine and cladribine both bound to the A(2A) receptor with a K                         (i) of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A(3) receptor with a K                         (i) of 10 μM, and none of these compounds bound to the A(2B) receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A(1) receptor. In addition, clofarabine, cladribine, and fludarabine were A(1) agonists (IC(50) 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K                         (i) > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.
authors.affiliation: College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard ST SE, Minneapolis, MN, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Jensen
authors.forename: L'Aurelle A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kirstein
authors.forename: Jatinder
authors.initials: J
authors.lastname: Lamba
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001087:Arabinonucleosides / Q000378:metabolism*; D001667:Binding, Competitive; D016466:CHO Cells; D017338:Cladribine / Q000378:metabolism*; D000077866:Clofarabine; D006224:Cricetinae; D003412:Cricetulus; D003603:Cytotoxins / Q000378:metabolism*; D006801:Humans; D058906:Purinergic P1 Receptor Agonists / Q000378:metabolism; D011869:Radioligand Assay; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D003603:Cytotoxins; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D017338:Cladribine; D000077866:Clofarabine; D014740:Vidarabine; C024352:fludarabine