Inhibition of lymphocyte-mediated cytolysis by adenosine analogs. Biochemical studies concerning mechanism of action

Wolberg, G.; Zimmerman, T.P.; Duncan, G.S.; Singer, K.H.; Elion, G.B.

Biochemical Pharmacology 27(10): 1487-1495

1978


ISSN/ISBN: 0006-2952
PMID: 212072
DOI: 10.1016/0006-2952(78)90105-3
Accession: 068524252

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Abstract
A number of adenosine (Ado) analogs inhibit murine lymphocyte-mediated cytolysis (LMC) in vitro at .mu.M concentrations. Those analogs which are substrates for adenosine deaminase were more inhibitory to LMC in the presence of erythro-9-(2-hydroxy-3-nonyl)adenine, an inhibitor of the deaminase. The inhibitory activity of most of these analogs (the exceptions being 2'-deoxyadenosine, 9-.beta.-D-arabinofuranosyladenine and 7-deazaadenosine) was markedly enhanced by an inhibitor (Ro 20-1724) of cyclicAMP phosphodiesterase. With the exceptions of 2-fluoroadenosine, 7-deazaadenosine and formycin A, the inhibition of LMC caused by the Ado analogs was fully reversible upon removal of the analogs from the medium. In general, the Ado analogs did not cause a reduction in the pool sizes of endogenous ribonucleoside 5'-triphosphates in the lymphocytes. Some inhibitory and non-inhibitory analogs were metabolized to their corresponding 5'-triphosphates. Lymphocytes pretreated with a reversible inhibitor of LMC, 2-aminoadenosine, retained most of the resultant 2-amino-ATP during subsequent incubation in analog-free medium. Most of the Ado analogs which were inhibitory to LMC caused a substantial elevation of lymphocyte cAMP; the magnitude of this elevation was enhanced by Ro 20-1724. Ado and many of its structural analogs may inhibit LMC by their ability to stimulate the formation and consequent build-up of cAMP in the cytotoxic lymphocytes. This stimulation of adenylate cyclase appears to result from the binding of an appropriate nucleoside to an adenosine receptor located on the membrane of the lymphocytes.