CYCLIC AMP-PHOSPHODIESTERASE AND EPIDERMAL MITOSIS

[摘要] The relationship between cyclic AMP-phosphodiesterase (cAMP-PDE) inhibition and inhibition of epidermal mitosis was examined for several compounds using a soluble, low Km PDE activity from hairless mouse skin and the G2 mouse ear mitosis assay. Orders of potency determined at IC50 levels (concentrations required for 50% inhibition) were SQ 20009 [1-ethyl-4-(isopropylidenehydrazino)-1H-pyrazolo[3,4,-b]pyridine-5-carboxylic acid ethyl ester hydrochloride] > RO 20-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone] > papaverine > bufexamac > indomethacin > theophylline > p-biphenylylacetic acid > or < glycyrrhetinic acid for inhibition of both PDE and mitosis. The disproportionately high antimitotic potency of puromycin relative to PDE inhibition was believed to reflect effects on protein biosynthesis. Activity of the 3 nonsteroidal anti-inflammatory agents (bufexamac, indomethacin and p-biphenylylacetic acid) was unrelated to their effect on prostaglandin synthesis in homogenates of hairless mouse skin. The epidermal antimitotic activity of the compounds tested may be related to their inhibition of cAMP-PDE; the results provide additional support for cAMP as a regulator of the G2 stage of the epidermal cell cycle.