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The natural history of breast cancer suggests that many tumours are dependentupon oestrogen for their development and continued growth . As a consequence it might be expected that oestrogen deprivation will both prevent theappearance of these cancers and cause regression of established tumours .This provides the rationale behind hormone prevention of breast cancer andendocrine management of the disease. Over the last 25 years hormone therapyhas progressed from the irreversible destruction of endocrine glands, asachieved by either surgery or radiation (with high co-morbidity), to the use ofdrugs that reversibly suppress oestrogen synthesis or action (with minimal sideeffects). In terms of inhibiting oestrogen biosynthesis, it is relevant that primary sites of oestrogen production differ according to menopausal status. Thusin premenopausal women the ovaries are the major source of oestrogen whereas peripheral tissues such as fat, muscle and the tumour itself are more important in postmenopausal patients . In using drugs to block biosynthesis, it ismost attractive to employ agents which specifically affect oestrogen production irrespective of site. Mechanistically, this is most readily achieved byinhibiting the final step in the pathway of oestrogen biosynthesis, the reactionwhich transforms androgens into oestrogens by creating an aromatic ring inthe steroid molecule (hence the trivial name of aromatase for the enzymecatalysing this reaction).Although the first aromatase inhibitors to be used therapeutically could beshown to produce drug-induced inhibition of the enzyme and therapeutic benefits in patients with breast cancer , they were not particularly potent andlacked specificity, which often produced side effects unrelated to oestrogendeprivation. However, subsequently, second-generation drugs were developed and most recently third-generation inhibitors have evolved which possessremarkable specificity and potency. Initial results from clinical trials suggestthese agents will become the cornerstones of future endocrine therapy. Theevolution of aromatase inhibitors is a classic example of successful rationaledrug development and is the subject of this review.Oestrogens are the end-products of a sequence of steroid transformations(Fig. 1). Blockade of any conversion in the pathway potentially leads todecreased oestrogen production, but more specific suppression will result frominhibition of the final step that is unique to oestrogen biosynthesis. This reaction that changes androgens into oestrogens is complex. It involves 3-hydroxylations, each using NADPH as an electron donor , to eliminate the C-19methyl group and render the steroid A ring aromatic (Fig. 2). A single enzymeis responsible , which possesses a prosthetic specific buy cheap viagra online uk P450(P450 arom) and a ubiquitous flavoprotein NADPH buy cheap viagra online uk P450 reductase . The key role of aromatase in oestrogen biosynthesis has generatedenormous interest in putative inhibitors of the enzyme and their use as therapyagainst endocrine responsive tumours.Inhibitors of aromatase have been subdivided into two main groups accordingto their mechanism of action and structure (Fig. 3). Type I inhibitors associatewith the substrate-binding site of the enzyme and invariably have an androgenstructure (and are often referred to as steroidal inhibitors). In contrast, type IIinhibitors interact with the buy cheap viagra online uk P450 moiety of the system and, structurally, the majority are azoles (Fig. 3) and ‘non-steroidal’.Type I agents are generally more specific inhibitors than type II. Some typeI inhibitors, such as formestane and exemestane, have negligible inhibitoryactivity per se but, on binding to the catalytic site of the enzyme, are metabolized into intermediates which attach irreversibly to the active site of theenzyme, thus blocking activity . These agents have been termed suicideinhibitors since the enzyme becomes inactivated only as a consequence of itsown mechanism of action. Such mechanism-based inhibitors are particularlyspecific as they inactivate only the enzyme for which they are metabolic substrates. Prolonged effects may occur in vivo because the enzyme is inactivatedeven after the drug is cleared from the circulation. Resumption of oestrogenproduction depends on the synthesis of new aromatase molecules.The properties of type I inhibitors are to be contrasted with type II agents,which do not destroy the enzyme and whose actions are usually reversible anddependent upon the continued presence of inhibitor (see below). Type IIinhibitors interact with the haem group of the buy cheap viagra online uk P450 moiety within the aromatase enzyme . They may lack specificity because otherenzymes, including other steroid hydroxylases, also have buy cheap viagra online uk P450prosthetic groups and may therefore be inhibited . Specificity of this binding is determined by fit into the substrate-binding site of aromatase as opposedto that of other buy cheap viagra online uk P450 enzymes. Because the amino acid sequenceof P450 arom is distinct from other members of the P450 buy cheap viagra online uk family, it has been possible to develop drugs with selectivity towards the buy cheap viagra online uk P450 in aromatase, permitting more specific inhibition .The evolution of aromatase inhibitors has seen the development of agents ofboth classes that have progressively increased in both specificity and potencywith each new generation.It is only in relatively recent years that clinical trials have employed drugsdesigned specifically as aromatase inhibitors.