Vorozole, a specific non-steroidal aromatase inhibitor

Wouters, Walter; Snoeck, Eric; Coster, R. De

doi:10.1007/bf00682743

Cited by 52 publications

(14 citation statements)

References 9 publications

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“…11 C-labeled vorozole, (S)-11 C-6-[(4-chlorophenyl)(1H-1,2,4-triazole-1-yl)methyl]-1-methyl-1H-benzotriazole (12), was developed as a PET tracer to investigate the in vivo distribution of aromatase in living animals and humans (13,14). Consistent with previous reports, we have shown that the accumulation of 11 C-vorozole was increased in several brain regions of rats and monkeys treated with anabolic steroids (15)(16)(17)(18), indicating that 11 C-vorozole is a useful molecular probe for aromatase imaging.…”

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confidence: 99%

PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole

Ozawa¹,

Takahashi²,

Akazawa³

et al. 2011

J Nucl Med

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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 Clabeled vorozole), based on a potent nonsteroidal aromatase inhibitor, has been developed as a tracer to investigate aromatase distribution in living animals and humans using a noninvasive PET technique. In the present study, we investigated gastric aromatase expression by means of PET with 11 C-vorozole. Methods: After bolus injection of 11 C-vorozole into the tail vein, emission scans were obtained for 90 min on male and female rats under isoflurane anesthesia. Displacement studies with unlabeled vorozole and autoradiographic analysis were conducted for demonstration of specific binding. Immunohistochemistry was performed to confirm aromatase expression. Results: PET scans revealed that 11 C-vorozole highly accumulated in the stomach and adrenal glands. Displacement studies and autoradiography demonstrated that aromatase was expressed in the stomach but that the accumulation of 11 C-vorozole in the adrenal glands might be through nonspecific binding. Immunohistochemical analysis revealed that aromatase is expressed in gastric parietal cells but not in adrenal glands. Moreover, the accumulation of 11 C-vorozole in the stomach was significantly increased in fatigued rats. Conclusion: These results suggest that the 11 C-vorozole PET technique is a useful tool for evaluation of gastric aromatase dynamics in vivo, which may provide important information for understanding the molecular mechanisms of gastric aromatase/estrogenrelated pathophysiological processes and for the development of new drugs.

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confidence: 99%

PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole

Ozawa¹,

Takahashi²,

Akazawa³

et al. 2011

J Nucl Med

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“…Previously, this compound has been reported as a competitive inhibitor of aromatase (Montellano, 1995). Although vorozole inhibits human CYP1B1, this compound is over 1000-fold more active for aromatase inhibition (Wouters et al, 1994). It is unclear why other nonsteroidal inhibitors were not found to be as effective as vorozole in decreasing the catalytic activity of CYP1B1.…”

Section: Discussionmentioning

confidence: 99%

CYP1B1 Is Not a Major Determinant of the Disposition of Aromatase Inhibitors in Epithelial Cells of Invasive Ductal Carcinoma

Rahman

Lax²,

Sutter³

et al. 2008

Drug Metab Dispos

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ABSTRACT:CYP1B1 and CYP19 (aromatase) have been shown to be expressed in breast tumors. Both enzymes are efficient estrogen hydroxylases, indicating the potential for overlapping substrate and inhibitor specificity. We measured the inhibition properties of aromatase inhibitors (AIs) against CYP1B1-catalyzed hydroxylation of 17␤-estradiol (E2) to determine whether CYP1B1 affects the disposition of AIs. In addition, we estimated the frequency of coexpression of these enzymes in breast tumor epithelium. Immunohistochemical analyses of CYP19 and CYP1B1 in a panel of 29 cases of invasive ductal carcinoma of the breast showed epithelial cell staining for CYP19 in 76% and for CYP1B1 in 97% of the samples. Statistical analysis showed no significant correlation (0.33) for positive expression of CYP19 and CYP1B1 (p > 0.07). CYP1B1 inhibition was determined for two steroidal inhibitors:formestane and exemestane and five nonsteroidal inhibitors: aminoglutethimide, fadrozole, anastrozole, letrozole, and vorozole. Of the seven compounds tested, only vorozole exhibited inhibition of CYP1B1 activity with IC 50 values of 17 and 21 M for 4-hydroxy estradiol and 2-hydroxy estradiol, respectively. The estimated K i values of vorozole for E2 4-and 2-hydroxylation were 7.26 and 6.84 M, respectively. Spectrophotometric studies showed that vorozole was a type II inhibitor of CYP1B1. This study shows that with the exception of vorozole, the aromatase inhibitors are selective for CYP19 relative to CYP1B1. Thus, although both CYP19 and CYP1B1 are expressed in a high percentage of breast cancers, CYP1B1 is not a major determinant of the disposition of AIs.CYP19 (aromatase) catalyzes the formation of the phenolic A ring of estrogens, converting androstenedione to estrone and testosterone to estradiol (Johnston and Dowsett, 2003). CYP19 is found in glandular and nonglandular tissues, including adrenal glands, ovaries, placenta, testes, adipose tissue, muscle, brain, normal breast, and breast cancer tissue. Important to this work, studies have shown that substantial levels of estrogens arise from aromatase activity in breast tissue (Miller, 1991;Bulun et al., 1993). CYP19 protein and activity have been detected in both the epithelial cells and surrounding stroma and adipose tissue of breast tumors (Esteban et al., 1992;Lu et al., 1996;Brodie et al., 1997;Oliveira et al., 2006;Miki et al., 2007). A recent study showed that although significant CYP19 immunoreactivity occurred in each of these cellular compartments of breast tumors, a significant positive correlation between biochemical activity and immunostaining was detected only for the epithelium (Sasano et al., 2005).Aromatase inhibitors (AIs) are drugs that inhibit CYP19, preventing the formation of estrogens. The AIs are subdivided into steroidal (type I) and nonsteroidal (type II) agents (Johnston and Dowsett, 2003;Miller, 2006). Type 1 agents are analogs of androgens that bind to CYP19 through either reversible or irreversible mechanisms, competing with the natural substrates. Type II i...

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“…In vitro studies have shown that Rivizor is greater than 1,000 times more potent than aminoglutethimide [29]. Furthermore, in a dose-ranging study, Rivizor 1-, 2.5-and 5-mg doses reduced serum estradiol by 89-91% [13].…”

Section: Discussionmentioning

confidence: 99%

Rivizor – A New Third-Generation Aromatase Inhibitor for the Treatment of Advanced Breast Cancer after Tamoxifen Failure

Goss¹,

Walde

Coster

et al. 1999

Oncology

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Rivizor^TM (vorozole) is a new, highly potent and selective third-generation aromatase inhibitor for treatment of advanced breast cancer. In an open-label study, 30 postmenopausal women failing tamoxifen therapy received Rivizor 2.5 mg once daily until disease progression. Rivizor produced clinical benefit (partial response or no change) in 16 of 27 evaluable patients (59.3%). Five patients (18.5%) had a partial response (UICC criteria) which lasted for a median of 15 months (range 14–42.5 months), 11 patients had disease stabilization for a median of 14 months (7–24 months), and 11 patients had disease progression. Median time to first response was 3.9 months (3–27.5 months): estimated median survival time for all patients was 22.8 months (2–52.8 months) and estimated median time to disease progression was 10.8 months (1.4–42.4 months). Estradiol levels decreased to below limits of detection from 1st month of treatment until study end. Androstenedione, 17α-hydroxyprogesterone, dehydroepiandrosterone, and free-testosterone levels were unaffected by Rivizor. ACTH stimulation tests demonstrated that Rivizor does not interfere with adrenal mineralocorticoid and glucocorticoid steroid synthesis. Adverse events were mild-to-moderate. Rivizor might be an effective and well-tolerated alternative treatment for postmenopausal advanced breast cancer patients following tamoxifen failure.

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Vorozole, a specific non-steroidal aromatase inhibitor

Cited by 52 publications

References 9 publications

PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole

PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole

CYP1B1 Is Not a Major Determinant of the Disposition of Aromatase Inhibitors in Epithelial Cells of Invasive Ductal Carcinoma

Rivizor – A New Third-Generation Aromatase Inhibitor for the Treatment of Advanced Breast Cancer after Tamoxifen Failure

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Vorozole, a specific non-steroidal aromatase inhibitor

Cited by 52 publications

References 9 publications

PET of Aromatase in Gastric Parietal Cells Using 11C-Vorozole

PET of Aromatase in Gastric Parietal Cells Using 11C-Vorozole

CYP1B1 Is Not a Major Determinant of the Disposition of Aromatase Inhibitors in Epithelial Cells of Invasive Ductal Carcinoma

Rivizor – A New Third-Generation Aromatase Inhibitor for the Treatment of Advanced Breast Cancer after Tamoxifen Failure

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PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole

PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole