Disease relevance of D00963

• PATIENTS AND METHODS: Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting [1].
• PATIENTS AND METHODS: Exemestane was administered at a dose of 25 mg/d orally until patients experienced disease progression [2].
• The impact of exemestane treatment on tumor-related signs and symptoms was assessed [2].
• Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers [1].
• Dose-response experiments with chondrosarcoma cultured cells were done with estrogen, androstenedione, and exemestane [3].
• Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer [4].

High impact information on D00963

• Primary objective was to evaluate the effect of exemestane on bone mineral density [1].
• PURPOSE: To evaluate potential detrimental effects of exemestane on bone and lipid metabolism [1].
• RESULTS: All of the third-generation oral aromatase inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and exemestane (steroidal, type I)--have now been tested in phase III trials as second-line treatment of postmenopausal hormone-dependent breast cancer [5].
• PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor [6].
• Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women [7].

Chemical compound and disease context of D00963

• PURPOSE: To assess the antitumor activity, safety, and hormone-suppressive effects of the irreversible aromatase inactivator, exemestane (Aromasin, Pharmacia & Upjohn, Kalamazoo, MI), administered as third-line hormone therapy to postmenopausal women with metastatic breast cancer that is refractory to tamoxifen and megestrol acetate [2].
• Endocrine effects of tamoxifen plus exemestane in postmenopausal women with breast cancer [8].
• Growth of chondrosarcoma cell cultures can be stimulated by adding estrogen or androstenedione, which can be inhibited by exemestane [3].
• In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, aminoglutethimide (n = 30), formestane (n = 12), and exemestane (n = 10), and the progestin megestrol acetate (n = 21) on plasma total homocysteine (tHcy) in patients suffering from advanced breast cancer [9].
• Preliminary data on letrozole and exemestane suggest that longer follow-up is needed for these two AIs before being able to fully assess their respective long-term CV toxicity profile [10].

Biological context of D00963

• Based on our results, a new clamping mechanism of substrate/exemestane binding to the active site is proposed [11].
• Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males [12].
• Oral clearance of exemestane averaged 602 L/h based on an average plasma exemestane AUC of 41.5 microg h/L (90% CI, 36.7-62.6) [13].
• The aim of this randomised study was to evaluate the longitudinal changes in body composition and lipid profiles in postmenopausal women switched from tamoxifen to exemestane [14].
• The Italian Consortium of Hereditary Breast Ovarian Cancer recently developed the Aromasin Prevention Study, a multicenter, double-blind, randomized, placebo-controlled phase III study evaluating the effect of the aromatase inhibitor exemestane for chemoprevention in postmenopausal women carriers of BRCA1/2 genetic predisposition [15].

Anatomical context of D00963

• CONCLUSIONS: Based on the absence of adverse endocrine effects with the addition of exemestane to tamoxifen therapy observed in this study, further clinical evaluation of the efficacy of this combination is warranted [8].
• DHT synthesis from androstenedione in MCF-7 cells was significantly inhibited by coculture with aromatase-positive stromal cells, which was significantly reversed by addition of aromatase inhibitor exemestane [16].
• Aromatase activity of ovarian microsomes (OAA) was reduced by 85%-93% after subcutaneous exemestane and by 25%-59% after MDL 18962, and was unaffected after atamestane [17].
• These cell lines are resistant to the aromatase inhibitors letrozole, anastrozole and exemestane and the anti-estrogen tamoxifen, for comparison [18].
• In order to find out to what extent exemestane and paclitaxel add to each other's effects when given concomitantly, the effect of the two drugs alone and in combination on the growth of various gynecological tumor cell lines was assessed [19].

Associations of D00963 with other chemical compounds

• Whereas first- and second-generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, the third-generation compounds anastrozole, exemestane, and letrozole were found to cause > or =98% aromatase inhibition [20].
• These data suggest that long-term safety profiles may differ between aromatase inhibitors, although comprehensive comparative data for letrozole and exemestane versus tamoxifen are lacking [21].
• Steroidal substrate analogs, such as formestane and exemestane, inactivate aromatase by binding irreversibly to it [22].
• Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation [23].
• Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada's Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib [23].

Gene context of D00963

• Eligible women will be followed thereafter in order to evaluate the efficacy of exemestane in reducing the incidental rate of breast cancer in unaffected postmenopausal carriers of BRCA1/2 mutations [15].
• Exemestane was a strong activator of mPXR ( approximately 22-fold activation) with only minor effect on hPXR ( approximately 5-fold activation) [24].
• METHODS: The expression of two angiogenic factors VEGF and Angiopoetin-1 were quantified at different concentrations of doxorubicin, docetaxel, tamoxifen, exemestane and letrozol on MCF-7 and T47D cells [25].
• A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer [26].
• A minor androgenic effect of exemestane is revealed by a significant suppression of sex hormone binding globulin (SHBG) [27].

Analytical, diagnostic and therapeutic context of D00963

• CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed [6].
• Combined with site-directed mutagenesis, several critical residues involved in enzyme catalysis and suicide inhibition by exemestane were evaluated [11].
• In a cross-over study, 12 were randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d with a 14-d washout period [12].
• PURPOSE: To optimize treatment strategies for postmenopausal breast cancer patients, we investigated the efficacy of the steroidal aromatase inhibitor exemestane alone or in combination with the antiestrogen tamoxifen in a xenograft model of postmenopausal breast cancer [28].
• However, the duration of overall success and times to disease progression and treatment failure were significantly prolonged with exemestane compared with megestrol [29].

References