631 Inhibition of 3′, 5′-cyclic nucleotide phosphodiesterase as a novel concept in tumour therapy

Abstract

A wide spectrum of human and animal tumour cell lines exhibit significantly lower cAMP levels than normal cells, as a consequence of strongly enhanced activities of a cAMP-specific phosphodiesterase isoenzyme (PDE). Inhibition of this isoenzyme by selective inhibitors results in a long lasting, concentration-dependent rise of intracellular cAMP, accompanied by marked growth inhibition. At higher concentrations of the inhibitor (>3<i>μ</i>M), induction of apoptosis becomes apparent, as detected by flow cytometry, confocal microscopy and ELISA-based determination of fragmented DNA in intact cells. Thus tumour-associated overexpression of a cAMP-specific PDE-isoenzyme in proliferating tumours offers a novel cellular target for selective antineoplastic therapy.