Cytotoxic purine nucleoside analogues bind to A 1, A 2A, and A 3 adenosine receptors

Kyle Jensen, L'Aurelle A Johnson, Pamala A Jacobson, Sonja Kachler, Mark N Kirstein, Jatinder Lamba, Karl Norbert Klotz

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21 Scopus citations


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 Ki of 17 and 15 ìM, respectively. Clofarabine was the only adenosine analogue to bind to the A 3 receptor with a Ki of 10 ìM, 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 (IC50 3.1, 30, and 30 ìM, 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.

Original languageEnglish (US)
Pages (from-to)519-525
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number5
StatePublished - May 2012

Bibliographical note

Funding Information:
Acknowledgments This research was supported by NIH T32 CA099936 (K.J. and L.J.) and Children’s Cancer Research Fund, Minneapolis, MN (K.J. and L.J.), and the Cancer Center Support Grant CA077598 (P.J. and M.K.).


  • A , A , A , A ligands
  • Adenosine receptors
  • Cladribine
  • Clofarabine
  • Fludarabine
  • Purine analogues


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