Ddp Anticancer Drugs

FIGURE 3.10 Mechanism of action of fulvestrant.

Interaction with coactivators

FIGURE 3.11 Binding of fulvestrant to the estrogen receptor. Comparison with estradiol binding.

binds to the ER which in the resting state has a single domain, called activating function (AF1), available for binding with coactivators and/or corepressors. After binding of estradiol, a second activating function (AF2) is exposed. The complex dimerizes and migrates to the cell nucleus, where it binds to the ERE of DNA, leading to recruitment of coactivators by both activation functions, subsequent stimulation of RNA polymerase activity and fully activated transcription. After the binding of SERMs, exemplified by tamoxifene (T) (Fig. 3.12B), activation of AF2 does not take place and therefore coactivator recruitment and transcription activation are only partial. The pure steroidal antagonists, like fulvestrant (Fig. 3.12C), bind to the ER with high affinity. This binding leads to a conformational change in the receptor resulting in the formation of a complex in which neither of the AF1 and AF2 activation functions is active. This complex does not dimerize, which facilitates its degradation. Also, migration to the cell nucleus is markedly reduced, preventing coactivator recruitment and transcription activation.

Trilostane is another steroidal compound that has been occasionally employed in the treatment of breast cancer and is now under reevaluation. It is an inhibitor of 3p-hydroxysteroid dehydrogenase, the enzyme that transforms pregnenolone into progesterone, a gestagen and also a biosynthetic precursor to all other types of steroidal hormones. Because of this property, it has been employed in disorders due to high levels of these hormones, such as Cushing's disease, which is characterized by high levels of cortisol. Further studies have shown that the antitumor effects of trilostane are partially due to the inhibition of steroidogenesis and also to allosteric inhibition of the estrogen, probably binding directly to the DNA-binding domain.17 Because it modulates ERs differently to tamoxifen and is able to influence internal cell signals and gene expression, it is undergoing clinical trials in

^radM Receptor ^"Ap

? dimerization w^tÚT



RNA polymerase

Transcription is fully activated

Both AF1 and AF2 are active

AF1 and AF2 recruit coactivators u

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