"Vorozole"

Initial Studies with ¹¹C-Vorozole PET Detect Overexpression of Intratumoral Aromatase in Breast Cancer. Aromatase inhibitors are the mainstay of hormonal therapy in estrogen receptor-positive breast cancer, although the response rate is just over 50% and in vitro studies suggest that only two thirds of postmenopausal breast tumors overexpress aromatase. The goal of the present study was to validate and optimize PET with C-vorozole for measuring aromatase expression in postmenopausal breast cancer in vivo. Ten newly diagnosed postmenopausal women with biopsy-confirmed breast cancer were administered C-vorozole intravenously, and PET emission data were collected between 40 and 90 min after injection. Tracer injection and scanning were repeated 2 h after ingestion of 2.5 mg of letrozole

Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [(11)C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor

Aromatase imaging with [N-methyl-11C]vorozole PET in healthy men and women. Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aimed to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathologic situations can be studied. (11)C-vorozole (111-296 MBq/subject) was injected intravenously in 13 men and 20 women (age range, 23-67 y). PET data were acquired over a 90-min period. Each subject had 4 scans, 2 per day separated by 2-6 wk, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases

, exemestane, vorozole, formestane,fadrozole, and, the most common aromatase inhibitor infertility treatment, letrozole. Animal studies have shownthat letrozole can cause birth defects if taken duringpregnancy, prompting Food and Drug Administration (FDA)warnings for its usage in pregnancy, but there is evidenceto support its safety when used to induce ovulation or OS(4, 31, 32).This guideline includes two

of patent) - an oestrogen antagonistExemestane (Trade name Aromasin) - an aromatase inhibitor which blocks the conversion of androgens into oestrogens. After the menopause most of your oestrogen comes from conversion of androgens, not from the ovariesAnastrozole (Trade name Arimidex) - another aromatase inhibitor widely used in the UKOther marketed aromatase inhibitors include Letrozole (Femara), Vorozole

by the potent aromatase inhibitor Vorozole (OVX+T+VOR). Serum estradiol concentration was significantly higher in OVX+T than in OVX or OVX+T+VOR females. Together these data demonstrate that treatment of OVX females with T increases sexual motivation and that these effects are mediated at least in part by non-gonadal aromatization of the androgen. Finally, assays of aromatase activity on brain and peripheral

In vivo visualization of aromatase in animals and humans. Aromatase catalyzes the last and obligatory step in the biosynthesis of estrogens across species. In vivo visualization of aromatase can be performed using positron emission tomography (PET) with radiolabeled aromatase inhibitors such as [(11)C]vorozole. PET studies in rats, monkeys and healthy human subjects demonstrate widespread

therapy consisting of selective estrogen-receptor modulators such as Tamoxifen, raloxifen, fulvestrant; aromatase inhibitors (anastrozole, letrozole, exemestane, vorozole); GnRH agonistsComparator(s)/controlEndocrine therapy onlyMain outcome(s)Progression-free survival and overall survivalAdditional outcome(s)SafetyData extraction (selection and coding)A data extraction algorithm will be constructed

with anesthetized rhesus monkeys were performed to analyze the dynamics in the brain. In vitro and in vivo studies using (11)C-cetrozole showed its superiority in brain aromatase imaging in terms of specificity and selectivity, compared with previously developed (11)C-vorozole. PET studies showed that (11)C-cetrozole had a higher signal-to-noise ratio, providing a sharper image than (11)C-vorozole, because the radioactive metabolite of (11)C-vorozole was taken up into the brain. High specific binding of (11)C-cetrozole was observed in the amygdala and hypothalamus, and we also noted binding in the nucleus accumbens of rhesus monkeys for the first time. These results suggest that PET imaging with newly developed (11)C-cetrozole is suitable for quantifying the expression of brain aromatase in vivo, possibly

. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, whereas a single injection of the aromatase inhibitor vorozole rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant

Inhibition of the in vivo conversion of androstenedione to estrone by the aromatase inhibitor vorozole in healthy postmenopausal women. Vorozole is a new, potent, and highly selective nonsteroidal aromatase inhibitor, which in animal and human studies was found to be about 1000-fold more potent than aminoglutethimide. Almost all aromatase-inhibiting activity resides in the dextro-enantiomer currently undergoing clinical trials. A marked decrease in circulating estrogens was found in several studies of healthy premenopausal women and male volunteers treated with the racemate, referred to as vorozole racemate. To further evaluate the aromatase-inhibiting potency of this drug, the in vivo conversion of androstenedione to estrone was studied in 12 healthy postmenopausal women. Four h after

Clinical and endocrine effects of the oral aromatase inhibitor vorozole in postmenopausal patients with advanced breast cancer. Vorozole is an orally active, nonsteroidal aromatase inhibitor. Twenty-four postmenopausal patients with advanced breast cancer who had relapsed after treatment with tamoxifen received three separate daily doses of vorozole (1, 2.5, and 5 mg) each for 1 month in a randomized, double-blind, phase II study. There was significant suppression (P < 0.001) of serum estradiol at all three doses (median reduction, 91, 90, and 89%, respectively). There was a significant trend (P = 0.02) for estradiol to be suppressed below the detection limit of the assay (3 pmol/liter) more frequently with an increasing dose of vorozole; 13, 31, and 40% respectively. Estrone and estrone

Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. To determine biologic differences, if any, between presurgical endocrine treatment with an aromatase inhibitor (vorozole) and tamoxifen in patients with postmenopausal primary breast cancer. Randomization was to 12 weeks of 2.5 mg of vorozole per day or 20 mg of tamoxifen per day, both orally. Clinical response was assessed monthly together with serum sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens (E1, E2, and E1S), lipids, insulin-like growth factor-1 (IGF-1), and bone metabolites (CrossLaps CTx). Tissue samples for Ki67, apoptotic index (AI), estrogen receptor

Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. North American Vorozole Study Group. To compare the efficacy and safety of vorozole (VOR) 2.5 mg once daily with that of megestrol acetate (MA) 40 mg four times per day as second-line therapy in postmenopausal women with advanced breast cancer whose disease progressed after tamoxifen treatment. A total of 452 patients were enrolled onto an open, multicenter, randomized phase III trial comparing VOR to MA for tumor response, safety, and quality of life (as indicated by the Functional Living Index-Cancer score). Vorozole produced a response rate of 9.7%, compared with 6.8% for MA (P = .24). Clinical benefit

with differing chemopreventive efficacy and mechanism(s) of action were examined: (a) hormonal treatments [tamoxifen, vorozole (an aromatase inhibitor), and ovariectomy]; (b) retinoid X receptor agonists (targretin, 9-cis retinoic acid, and UAB30); (c) inducers of drug-metabolizing enzymes (indole-3-carbinol, 5,6 benzoflavone, and diindoylmethane); (d) agents that alter signal transduction (R115777

Effects of androgens on aromatase activity and 11C-vorozole binding in granulosa cells in vitro. Locally produced androgens and estrogens are important in the hormonal regulation of follicular development. The present study aimed to further elucidate the mechanism through which androgens exert their ambivalent effects on aromatization. Non-cultured human granulosa-luteal cells (GC) were treated with different concentrations of androstenedione (A4), testosterone (T), 5alpha-androstane-3,17-dione (5alpha-A) and dihydrotestosterone (DHT). The effects on aromatase activity were evaluated in a tritiated water assay (incubation time 2 h) and the availability of aromatase active sites was measured in a radiotracer-binding assay using the non-steroidal competitive aromatase inhibitor [11C]-vorozole

. Research: The authors state that direct comparisons are needed to distinguish between letrozole and other, newer aromatase inhibitors such as anastrozole and vorozole. The authors further state that the long-term tolerability profile of aromatas..

Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone-dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase-sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub -nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole-derived sulfamates and a vorozole-based sulfamate were designed and biologically evaluated in JEG-3 cells to reveal structure-activity relationships. Amongst achiral and racemic compounds, 2-bromo-4-(2-(4-cyanophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)phenyl sulfamate

PET of aromatase in gastric parietal cells using 11C-vorozole. Aromatase is a rate-limiting enzyme for estrogen biosynthesis and has been implicated in pathophysiological states of various diseases via estrogen production. This enzyme is known to be widely distributed in extragonadal and gonadal tissues including the stomach. In contrast to circulating estrogen, the functional role of gastric aromatase/estrogen has not been elucidated in detail, because there is no efficient methodology to investigate spatiotemporal changes of gastric aromatase/estrogen in vivo. Recently, (S)-(11)C-6-[(4-chlorophenyl)(1H-1,2,4-triazole-1-yl)methyl]-1-methyl-1H-benzotriazole ((11)C-labeled vorozole), based on a potent nonsteroidal aromatase inhibitor, has been developed as a tracer to investigate aromatase