Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifty to sixty percent of postmenopausal women with estrogen receptor positive metastatic breast cancer respond objectively to surgical ablation of the pituitary or adrenal glands. Several investigators have recently developed medical alternatives to surgical ablative therapy for these patients. This review describes one of these strategies, the inhibition of estrogen synthesis with the enzyme inhibitor aminoglutethimide (AG). Aminoglutethimide blocks several cytochrome P-450-mediated steroid hydroxylation steps including those required for cholesterol to pregnenolone conversion and for the aromatization of androgens to estrogens. In women with metastatic carcinoma, a regimen including 1,000 mg of AG and 40 mg of hydrocortisone as replacement glucocorticoid was administered daily. Clinical studies revealed a 32% objective response rate to AG-HC in unselected patients, and a 52% response in women with estrogen receptor positive tumors. Randomized trials revealed that AG-HC produced objective regression as frequently as surgical adrenalectomy (Ag-HC + 53% vs. surgical adrenalectomy (43%, p = NS), and as surgical hypophysectomy (AG-HC 47% vs. hypox 21%, p + NS). Comparison of AG-HC administration with antiestrogen treatment suggested an equal rate of response to either therapy. Preliminary data document responses to AG in antiestrogen-resistant patients. Current studies do not allow precise recommendations regarding the sequence of use of antiestrogens and AG-HC.
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PMID:Suppression of estrogens with aminoglutethimide and hydrocortisone (medical adrenalectomy) as treatment of advanced breast carcinoma: a review. 629 27

Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.
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PMID:Use of aromatase inhibitors in breast carcinoma. 1073 91

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.
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PMID:Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen. 2291 89