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Chemical Compound Review

rac-VOROZOLE     6-[(4-chlorophenyl)-(1,2,4- triazol-1...

Synonyms: CHEMBL100749, CCRIS 7482, CCRIS 8867, SureCN1552681, CHEBI:263462, ...
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Disease relevance of R-83839

  • During 7 days preceding mastectomy, 11 postmenopausal breast cancer patients were treated with 2.5 mg of vorozole once daily [1].
  • Twenty-nine eligible women with estrogen receptor-positive or unknown disease were treated with 2.5 mg vorozole once daily p.o. until disease progression [2].
  • This chemopreventive effect was accompanied by significant increases in body weight gain in the animals treated with vorozole when compared with control rats [3].
  • A relative decrease of femoral inner and outer diameters compared with Sham and Base was observed in both Orch groups and in Sham + VOR, suggesting that both orchidectomy and VOR-treatment inhibited periosteal bone formation and endosteal bone resorption [4].
  • Here we evaluated for the first time the expression of cell death-related proteins Bcl-2 and Bax in hyperplastic, premalignant (carcinoma in situ), or malignant (carcinoma) lesions of mammary carcinogenesis; we also assessed whether these proteins are involved in mediating Vz-induced cell death in tumors [5].

Psychiatry related information on R-83839

  • Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, whereas a single injection of the aromatase inhibitor vorozole rapidly inhibits this behavior [6].

High impact information on R-83839


Chemical compound and disease context of R-83839


Biological context of R-83839

  • Preliminary studies to determine the applicability of this gene expression approach for detecting potential biomarkers for cancer chemoprevention was evaluated in rat mammary tumors obtained from animals treated with vorozole, a potent aromatase inhibitor [12].
  • The decrease of cancellous bone density in Sham + VOR was lower than in the orchidectomized animals [4].
  • In animals with established mammary tumors, Vz induced apoptotic cell death, which was primarily associated with a decrease in Bcl-2 and, to a lesser extent, with a decrease in Bax [5].
  • From this model we have postulated a membrane-associated hydrophobic region of aliphatic and aromatic residues involved in substrate recognition, a redox-partner binding region that may be unique compared to other P450s, as well as residues involved in active site orientation of substrates and an inhibitor of P450arom, namely vorozole [13].
  • Vorozole also inhibited appetitive sexual behavior measured by the social proximity response (P < 0.05, g = 0.534) or rhythmic cloacal sphincter movements (P < 0.001, g = 0.408) [14].

Anatomical context of R-83839

  • Bone area, mineral content, and density of both femora and lumbar vertebrae, measured by DXA, were decreased to a similar extent by VOR and Orch (bone mineral content of the femur was 467 +/- 18 mg in Orch and 461 +/- 10 mg in Sham +/- VOR vs. 521 +/- 11 mg in Sham; P < 0.001) [4].
  • Vorozole (1.25 mg/kg) administration for 28 days had differential, compartmentalized uterine effects, producing an increase (P<0.05) in epithelial cell height, a decrease (P<0.05) in stromal size, but no change in myometrial thickness [15].
  • On the other hand, the inhibition of the 17,20-lyase of rat testis observed at concentrations greater than or equal to 0.5 microM, originates rather from R 83842 [16].
  • Up to 10 microM, R 76713 and its enantiomers have no statistically significant effect on the regio- and stereoselective oxidations of testosterone in male rat liver microsomes [16].
  • In FSH-stimulated rat granulosa cells, vorozole inhibited aromatase activity with an IC50-value of 1.4 +/- 0.5 nM [17].

Associations of R-83839 with other chemical compounds


Gene context of R-83839

  • These data, which are considered hypothesis generating, provide evidence that low doses of vorozole in the diet select for mammary carcinomas with an increased ER positive phenotype [11].
  • All carcinomas from vorozole-treated rats expressed PR (2.5-60.2%) and correlation between ER and PR content was numerically greater in carcinomas from vorozole-treated animals (r = 0.42, p = 0.09) [11].
  • Although aromatase inhibitors, CGS 20267 and vorozole did not modify the in vivo growth of the nine pancreatic carcinoma cell lines significantly, the combined use of aromatase inhibitors with LEU exhibited a synergistic antitumor effect on Capan-2-bearing mice [22].
  • In LHRH/ACTH-injected male rats and in rats fed a sodium-deprived diet, single oral administration of up to 10 mg/kg vorozole did not affect plasma levels of testicular and adrenal steroids [17].
  • Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment [19].

Analytical, diagnostic and therapeutic context of R-83839

  • R 76713, the racemate, (+)-vorozole (both at 2.5 mg/kg twice a day), and ovariectomy all similarly reduced tumor growth at 42 days by 90% or more, lowered the number of existing tumors, and prevented the appearance of new tumors [23].
  • 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 [8].
  • In the vorozole group, the correlations of proportional changes in Ki67 at 2 weeks with tumor volume changes and clinical response at 12 weeks were not significant (P =.09) and marginally significant (P =.04), respectively [7].
  • When genes exhibiting differential expression as determined by CCLS or cDNA microarray analysis were examined in control and vorozole-treated tumors, expression of 19 genes was found to be modulated significantly in tumors treated with vorozole [12].
  • As expected, femoral length increased compared with Base, but orchidectomy reduced the relative growth of the femur whereas VOR did not influence femoral length [4].


  1. Inhibition of breast cancer tissue aromatase activity and estrogen concentrations by the third-generation aromatase inhibitor vorozole. de Jong, P.C., van de Ven, J., Nortier, H.W., Maitimu-Smeele, I., Donker, T.H., Thijssen, J.H., Slee, P.H., Blankenstein, R.A. Cancer Res. (1997) [Pubmed]
  2. Phase II study of vorozole (R83842), a new aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression on tamoxifen. Goss, P.E., Clark, R.M., Ambus, U., Weizel, H.A., Wadden, N.A., Crump, M., Walde, D., Tye, L.M., De Coster, R., Bruynseels, J. Clin. Cancer Res. (1995) [Pubmed]
  3. Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats. Lubet, R.A., Steele, V.E., Casebolt, T.L., Eto, I., Kelloff, G.J., Grubbs, C.J. Carcinogenesis (1994) [Pubmed]
  4. Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats. Vanderschueren, D., van Herck, E., Nijs, J., Ederveen, A.G., De Coster, R., Bouillon, R. Endocrinology (1997) [Pubmed]
  5. Bcl-2 and Bax are differentially expressed in hyperplastic, premalignant, and malignant lesions of mammary carcinogenesis. Shilkaitis, A., Graves, J., Mehta, R.R., Hu, L., You, M., Lubet, R., Steele, V., Kelloff, G., Christov, K. Cell Growth Differ. (2000) [Pubmed]
  6. Rapid decreases in preoptic aromatase activity and brain monoamine concentrations after engaging in male sexual behavior. Cornil, C.A., Dalla, C., Papadopoulou-Daifoti, Z., Baillien, M., Dejace, C., Ball, G.F., Balthazart, J. Endocrinology (2005) [Pubmed]
  7. Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. Harper-Wynne, C.L., Sacks, N.P., Shenton, K., MacNeill, F.A., Sauven, P., Laidlaw, I.J., Rayter, Z., Miall, S., Howes, A., Salter, J., Hills, M.J., Lowe, F.M., A'Hern, R., Nasiri, N., Doody, D., Iqbal, J., Dowsett, M. J. Clin. Oncol. (2002) [Pubmed]
  8. Clinical and endocrine effects of the oral aromatase inhibitor vorozole in postmenopausal patients with advanced breast cancer. Johnston, S.R., Smith, I.E., Doody, D., Jacobs, S., Robertshaw, H., Dowsett, M. Cancer Res. (1994) [Pubmed]
  9. 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. Goss, P.E., Winer, E.P., Tannock, I.F., Schwartz, L.H. J. Clin. Oncol. (1999) [Pubmed]
  10. The third-generation non-steroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer. Hamilton, A., Piccart, M. Ann. Oncol. (1999) [Pubmed]
  11. Effect of the aromatase inhibitor vorozole on estrogen and progesterone receptor content of rat mammary carcinomas induced by 1-methyl-1-nitrosourea. Knott, K.K., McGinley, J.N., Lubet, R.A., Steele, V.E., Thompson, H.J. Breast Cancer Res. Treat. (2001) [Pubmed]
  12. Altered gene expression profile in chemically induced rat mammary adenocarcinomas and its modulation by an aromatase inhibitor. Wang, Y., Hu, L., Yao, R., Wang, M., Crist, K.A., Grubbs, C.J., Johanning, G.L., Lubet, R.A., You, M. Oncogene (2001) [Pubmed]
  13. A three-dimensional model of aromatase cytochrome P450. Graham-Lorence, S., Amarneh, B., White, R.E., Peterson, J.A., Simpson, E.R. Protein Sci. (1995) [Pubmed]
  14. Rapid effects of aromatase inhibition on male reproductive behaviors in Japanese quail. Cornil, C.A., Taziaux, M., Baillien, M., Ball, G.F., Balthazart, J. Hormones and behavior. (2006) [Pubmed]
  15. Effects of oral administration of tamoxifen, toremifene, dehydroepiandrosterone, and vorozole on uterine histomorphology in the rat. Nephew, K.P., Osborne, E., Lubet, R.A., Grubbs, C.J., Khan, S.A. Proc. Soc. Exp. Biol. Med. (2000) [Pubmed]
  16. R 76713 and enantiomers: selective, nonsteroidal inhibitors of the cytochrome P450-dependent oestrogen synthesis. Vanden Bossche, H., Willemsens, G., Roels, I., Bellens, D., Moereels, H., Coene, M.C., Le Jeune, L., Lauwers, W., Janssen, P.A. Biochem. Pharmacol. (1990) [Pubmed]
  17. Pharmacology of vorozole. Wouters, W., Van Ginckel, R., Krekels, M., Bowden, C., De Coster, R. J. Steroid Biochem. Mol. Biol. (1993) [Pubmed]
  18. Inhibition of the in vivo conversion of androstenedione to estrone by the aromatase inhibitor vorozole in healthy postmenopausal women. van der Wall, E., Donker, T.H., de Frankrijker, E., Nortier, H.W., Thijssen, J.H., Blankenstein, M.A. Cancer Res. (1993) [Pubmed]
  19. Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model. Lubet, R.A., Steele, V.E., DeCoster, R., Bowden, C., You, M., Juliana, M.M., Eto, I., Kelloff, G.J., Grubbs, C.J. Carcinogenesis (1998) [Pubmed]
  20. Tamoxifen resistant and refractory breast cancer: the value of aromatase inhibitors. Goss, P.E., Strasser, K. Drugs (2002) [Pubmed]
  21. Inhibitors of aromatase prevent degradation of the enzyme in cultured human tumour cells. Harada, N., Hatano, O. Br. J. Cancer (1998) [Pubmed]
  22. Tissue-type plasminogen activator predicts endocrine responsiveness of human pancreatic carcinoma cells. Kuramoto, M., Yamashita, J., Ogawa, M. Cancer (1995) [Pubmed]
  23. Antitumoral and endocrine effects of (+)-vorozole in rats bearing dimethylbenzanthracene-induced mammary tumors. De Coster, R., Van Ginckel, R.F., Callens, M.J., Goeminne, N.K., Janssens, B.L. Cancer Res. (1992) [Pubmed]
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