Aspirin, arguably the world's favourite drug, has been around since the late nineteenth century, but it wasn't until the late 1970s that its ability to inhibit prostaglandin production by the cyclooxygenase enzyme was identified as the basis of its therapeutic action. Early hints of a second form of the cyclooxygenase that was differentially sensitive to other aspirin-like drugs ultimately ushered in an exciting era of drug discovery, culminating in the introduction of an entirely new generation of anti-inflammatories. This article reviews the story of this discovery and looks at the future of cyclooxygenase pharmacology.

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1 Recruitment to activated tyrosine kinase growth factor receptors of Grb2 and p21 ras leads to downstream activation of the kinases Raf, MAPK/Erk kinase (Mek) and, subsequently, extracellular signal-regulated kinase (Erk). Activated Erk phosphorylates speci®c serine residues within cytosolic phospholipase A 2 (PLA 2 ), promoting enzyme translocation to membranes and facilitating liberation of arachidonic acid (AA). 2 In the A549 human adenocarcinoma cell line dexamethasone inhibited epidermal growth factor (EGF)-stimulated cytosolic PLA 2 (cPLA 2 ) activation and AA release by blocking the recruitment of Grb2 to the activated EGF receptor (EGF-R) through a glucocorticoid receptor (GR)-dependent (RU486-sensitive), transcription-independent (actinomycin-insensitive), mechanism. 3 The dexamethasone-induced block of Grb2 recruitment was parallelled by changes in phosphorylation status and subcellular localization of lipocortin 1 (LC1) and an increase in the amount of the tyrosine phosphoprotein co-localized with EGF-R. 4 Like dexamethasone, peptides containing E-Q-E-Y-V from the N-terminal domain of LC1 also blocked ligand-induced association of Grb2, p21 ras and Raf. 5 Our results point to an unsuspected rapid eect of glucocorticoids, mediated by occupation of GR but not by changes in gene transcription, which is brought about by competition between LC1 and Grb2 leading to a failure of recruitment o signalling factors to EGF-R