strogen-dependent transcription while the other aims at depriving the system of estrogen by inhibiting estrogen biosynthesis. In the first case, selective estrogen receptor modulators (SERM) and antagonists have been developed. Among the most widely used SERM is the non-steroidal anti-estrogen tamoxifen (TAM). Initially considered a pure antagonist, it is now realized that it has mixed antagonist/agonist functions acting as an antagonist in breast cancer cells but as a partial agonist in bone and the cardiovascular system. TAM is extensively metabolized and both primary and secondary metabolites appear to have higher potencies than the parent compound. Tamoxifen and its metabolites bind the estrogen receptors Esr1 and 2 (ER), albeit with somewhat different affinities. The suppressed transcriptional activity of the receptors results in suppressed tumor growth as genes regulated by estrogen are involved in proliferation, angiogenesis, anti-apoptosis, among others. The second pharmacological approach involves the development of aromatase inhibitors (AI). The cytochrome P450 aromatase complex is the rate-limiting enzyme of estrogen biosynthesis. Three generation of inhibitors have been developed; the third generation is currently being used. The inhibitors can be further classified as type I or type II depending on whether the inhibition is irreversible or reversible. An example of third generation type I drug is the steroidal agent exemestane; examples of type II third generation drugs include the non-steroidal agents anastrozole and letrozole. Aromatase converts androstenedione and testosterone to estrone and estradiol, respectively. Exemestane which is an analog of androstenedione is recognized as substrate and believed to be converted into a reactive intermediate that covalently and irreversibly binds to the enzyme's substrate site permanently inactivating it. Non-steroidal agents bind non-covalently to the aromatase heme moiety thus occupying the substrate-binding site and this action is reversible as endogenous substrate can competitively displace them. Both SERM and AI exhibit selected side effects and resistance to their actions is developed over time.
[Click here to browse drug pathway listed by categories at PharmGKB: anti-estrogen pathways are under 'Antineoplastic and Immunomodulating Agents']...(less)