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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Pre-clinical and clinical review of vorozole, a new third generation aromatase inhibitor.

Vorozole (Rivizor), is a triazole derivative and one of the new, third generation aromatase inhibitors. Vorozole causes reversible inhibition of cytochrome P450 aromatase with the majority of the aromatase inhibition activity attributable to the dextro-isomer. In vitro the IC50 against human placental aromatase and in cultured rat ovarian granulosa cells is 1.38 and 0.44 nM, respectively. Vorozole is selective and does not effect other cytochrome P450-dependent reactions at concentrations up to at least 500-fold the aromatase inhibiting concentration. In vitro vorozole, at concentrations of up to 10 microM, does not exhibit agonistic or antagonistic effects on steroid receptors including the estrogen, progestin, androgen and glucocorticoid receptors. In vivo vorozole produces dose-dependent inhibition of aromatase and reduces circulating estrogen levels. Vorozole has been shown to inhibit intratumoral aromatase activity in postmenopausal breast cancer patients pretreated for 7 days prior to undergoing mastectomy. Tissue estrone and estradiol levels were also shown to be decreased by 64% and 80%, respectively. In four phase II clinical trials, vorozole produced response rates of 18-33% corresponding to selective inhibition of estradiol. Vorozole has been examined in large, randomized multi-centre, controlled trials against both megestrol acetate (MA) and aminoglutethimide (AG) plus hydrocortisone. Against MA, response rates were comparable (10.5% vorozole; 7.6% MA) however, a trend towards improvement in median duration of response for vorozole (18.2 versus 12.5 months; p = 0.07) was shown. No differences in time to progression or survival were noted. Significant and persistent weight gain associated with MA administration was the most notable difference in tolerability between the two agents. Against AG, vorozole showed a higher response rate (23 % versus 18%) however this did not reach statistical significance (p = 0.085). No differences in duration of response, time to progression and survival were noted. A significantly better Functional Living Index-Cancer (FLIC) quality of life score was associated with vorozole compared to AG. Vorozole is a specific, selective and potent aromatase inhibitor and useful for postmenopausal patients with advanced breast cancer.[1]

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