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PMID: 10960067 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Study of A(2A) adenosine receptor gene deficient mice reveals that adenosine analogue CGS 21680 possesses no A(2A) receptor-unrelated lymphotoxicity.

British journal of pharmacology ·Vol. 131 ·No. 1 ·2000-09-00 ·Pages 43-50

Apasov SG, Chen JF, Smith PT, Schwarzschild MA, Fink JS, Sitkovsky MV

Abstract

Cell surface A(2A) adenosine receptor (A(2A)R) mediated signalling affects a variety of important processes and adenosine analogues possess promising pharmacological properties. Demonstrating the receptor specificity of potentially lymphotoxic adenosine-based drugs facilitates their development for clinical applications. To distinguish between the receptor-dependent and -independent lymphotoxicity and apoptotic activity of adenosine and its analogues we used lymphocytes from A(2A)R-deficient mice. Comparison of A(2A)R-expressing (+/+) and A(2A)R-deficient (-/-) cells in cyclic AMP accumulation assays confirmed that the A(2A)R agonist CGS 21680 is indeed selective for A(2A) receptors in T-lymphocytes. Incubation of A(2A)R-expressing thymocytes with extracellular adenosine or CGS 21680 in vitro results in the death of about 7-15% of thymocytes. In contrast, no death was induced in parallel assays in cells from A(2A)R-deficient mice, providing genetic evidence that CGS 21680 does not display adenosine receptor-independent intracellular cytotoxicity. The A(2A) receptor-specific lymphotoxicity of CGS 21680 is also demonstrated in a long-term (6-day) in vitro model of thymocyte positive selection where addition of A(2A)R antagonist ZM 241,385 did block the effects of CGS 21680, allowing the survival of T cells. The use of cells from adenosine receptor-deficient animals is proposed as a part of the screening process for potential adenosine-based drugs for their receptor-independent cytotoxicity and lymphotoxicity.

MeSH Terms
Adenosine/analogs & derivatives,toxicity Animals Apoptosis/drug effects Cell Survival/drug effects Cyclic AMP/metabolism Mice Phenethylamines/toxicity Receptors, Antigen, T-Cell/physiology Receptors, Purinergic P1/deficiency,physiology T-Lymphocytes/drug effects
Chemicals
Phenethylamines Receptors, Antigen, T-Cell Receptors, Purinergic P1 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine Cyclic AMP Adenosine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Apasov S G
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892-1892, USA.
Chen J F
Smith P T
Schwarzschild M A
Fink J S
Sitkovsky M V
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0703532
Published
2000-09-00
Pages
43-50
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1572291
Subset
IM
Grants
NIDA NIH HHS · DA07496 · United States
External Links
PubMed source DOI: 10.1038/sj.bjp.0703532 PMC Full Text View journal details
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