This approach is best illustrated by inhibitors of aromatase or 5a-reductase activity. The aromatase enzyme converts androgens to oestrogens and is the last step of the synthetic cascade. Its inhibition represents the most specific method of blocking oestrogen production. Because oestrogen biosynthesis can occur in non-endocrine tissue such as adipose tissue and malignant tumours themselves (particularly in post-menopausal women), aromatase inhibitors have the potential to suppress oestrogen levels beyond that achievable by surgical ablation of classical endocrine organs. Two major types of inhibitors have been developed:
♦ Steroidal or type I inhibitors, which interfere with the attachment of androgen substrate to the catalytic site.
♦ Non-steroidal type II inhibitors, which interfere with the enzyme's cytochrome p450 prosthetic group.
Early type II inhibitors such as aminoglutethimide were neither potent nor specific, inhibiting other steroid-metabolizing enzymes that had a similar cytochrome p450 prosthetic group. Triazole drugs (anastrozole, letrozole, vorozole) are 2000-fold more potent than aminoglutethimide and have differential affinity towards aromatase cytochrome p450 with highly selective inhibition of oestrogen biosynthesis. These drugs can reduce circulating oestrogens in post-menopausal women to undetectable levels without influencing other steroid hormones.
Amongst type I inhibitors, formestane and exemestane are thought to act as 'suicide' inhibitors, blocking aromatase irreversibly through their own metabolism into active intermediates by the enzyme; oestrogen biosynthesis can only be resumed when aromatase molecules are synthesized de novo.
However, aromatase inhibitors may not influence the growth of hormone-dependent tumours. Oestrogenic effects are mediated through non-classical oestrogens such as:
♦ Adrenal 5-androgens.
♦ Dietary phyto-oestrogens.
♦ Industrial pesticides.
In terms of androgens, 5a-dihydrostesterone has much greater biological activity in the prostate than its precursor, testosterone. There has been interest in developing 5a-reductase inhibitors such as finasteride. However, they appear more useful for benign prostatic conditions than for cancer.
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