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Brueggemeier, Robert W
Seminars in reproductive medicine, 02/2004, Letnik: 22, Številka: 1Journal Article
Estrogens are involved in numerous physiological processes and have crucial roles in certain disease states such as mammary carcinoma. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in breast tissue, and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. Competitive aromatase inhibitors are molecules that compete with the substrate androstenedione for noncovalent binding to the active site of the enzyme to decrease the amount of product formed. Steroidal inhibitors that have been developed to date build upon the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid. Nonsteroidal aromatase inhibitors can be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase inhibitors are steroidal inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase. Both steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitor aminoglutethimide has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce potent aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, are approved for clinical use in postmenopausal patients with advanced hormone-dependent breast cancer or in patients failing antiestrogen therapies. Several clinical studies of aromatase inhibitors are currently focusing on the use of these agents in the adjuvant setting for the treatment of early breast cancer.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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