Relative potencies of flutamide and casodex: preclinical studies.
Abstract
Abstract After 3 h of incubation at room temperature, hydroxyFlutamide, the active metabolite of Flutamide (Eulexin), and Casodex (bicalutamide), an analog of Flutamide, have comparable potency to displace [3H]R1881 from the human prostate and rat ventral prostate androgen receptors contrary to the previous claims that Casodex was four times more potent using different incubation conditions. Binding data, in fact, must be interpreted with caution, since they are very much dependent upon the duration and temperature of incubation. In the more appropriate intact cell situation, hydroxyFlutamide is approximately three times more potent than Casodex at inhibiting dihydrotestosterone-stimulated proliferation of androgen-sensitive mouse Shionogi carcinoma cells in vitro. Under in vivo conditions, in the orchiectomized rat supplemented with androstenedione implants, Flutamide is about three times more potent than Casodex at inhibiting ventral prostate and seminal vesicle weight. When both compounds were administered for 7 days to intact rats, Flutamide and Casodex showed similar apparent potency. However, taking into account the much higher plasma levels of testosterone and dihydrotestosterone in intact animals treated with Flutamide compared with those treated with Casodex, the estimated potency of Flutamide in the intact rat is also at least three times higher than that of Casodex. The present data, contrary to previous claims based upon the inappropriate intact rat model clearly show that Flutamide is at least three times more potent than Casodex in rat and mouse tissues. These data are opposite to those obtained in the inappropriate intact rat model where Casodex was reported to be five to ten times more potent than Flutamide. Using more appropriate models of androgen action, the present data thus indicate a 15- to 30-fold lower estimate of the potency of Casodex. Since the choice of the dose of Casodex to be used for the treatment of prostate cancer patients is based upon such a large overestimate of the true potency of Casodex, the present data should help the choice of a more appropriate dose of this antiandrogen for the treatment of prostate cancer. Endocrine-Related Cancer (1996) 3 229-241
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Androgens originating from neighboring or distant cells that transform DHEA into androgens can affect other cells after diffusion.
“the androgens originating from neighboring or distant cells that possess the required mechanisms to transform DHEA into androgens in sufficient amounts to affect other cells after diffusion from their site of synthesis (271).”
From Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone (2003) · cites this paper as [271]
DHEA exerts an inhibitory effect on growth of ZR-75-1 cancer cells under in vivo conditions in nude mice.
“DHEA exerts an inhibitory effect on the growth of the same cancer cells under in vivo conditions in nude mice, the androgens originating from neighboring or distant cells that possess the required mechanisms to transform DHEA into androgens in sufficient amounts to affect other cells after diffusion from their site of synthesis (271).”
From Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone (2003) · cites this paper as [271]
Cited by
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Labrie, F., Luu-The, V., Labrie, C., Bélanger, A., Simard, J., Lin, S.-X., & Pelletier, G. (2003) · Endocrine Reviews · doi:10.1210/er.2001-0031 · Cited by 544 · see citing works
“Moreover, despite the fact that human ZR-75-1 breast cancer cells do not express 3 -HSD and are thus unable to synthesize androgens, thus explaining the stimulatory effect of DHEA on the growth of these cells under in vitro conditions (253), DHEA exerts an inhibitory effect on the growth of the same cancer cells under…”
BackgroundSelf-citationInhibitors of 17β-Hydroxysteroid Dehydrogenases
Poirier, D. (2003) · Current Medicinal Chemistry · doi:10.2174/0929867033368222 · Cited by 177 · see citing works
An evaluation of bicalutamide in the treatment of prostate cancer
Schellhammer, P. F. (2002) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.3.9.1313 · Cited by 100 · see citing works
“However, conflicting results regarding the relative receptor-binding affinity and potency of the non-steroidal antiandrogens have been published [26].”
ResultBlockade of testicular and adrenal androgens in prostate cancer treatment
Labrie, F. (2011) · Nature Reviews Urology · doi:10.1038/nrurol.2010.231 · Cited by 88 · see citing works
“the actual affinity of these compounds for the androgen receptor is low”
BackgroundSelf-citationPrognostic value and expression of p21(waf1/cip1) protein in prostate cancer
Aaltomaa, S. H., Lipponen, P., Eskelinen, M. J., Ala‐Opas, M., & Kosma, V. (1999) · The Prostate · doi:10.1002/(sici)1097-0045(19990401)39:1 · Cited by 119 · see citing works
Tremblay, M. R., Luu-The, V., Leblanc, G., Noël, P., Breton, E., Labrie, F., & Poirier, D. (1999) · Bioorganic & Medicinal Chemistry · doi:10.1016/s0968-0896(98)00260-0 · Cited by 43 · see citing works
Self-citationBicalutamide in Advanced Prostate Cancer
Goa, K. L., & Spencer, C. M. (1998) · Drugs & Aging · doi:10.2165/00002512-199812050-00006 · Cited by 41 · see citing works
“Binding affinity of bicalutamide was similar to or lower than that of hydroxyflutamide in studies by Luo and colleagues,[29] who found much weaker binding affinities for both drugs than has been reported by most other investigators.”
ResultSimard, J., Singh, S. M., & Labrie, F. (1997) · Urology · doi:10.1016/s0090-4295(97)00029-0 · Cited by 40 · see citing works
Self-citationBydal, P., Luu-The, V., Labrie, F., & Poirier, D. (2008) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2008.03.020 · Cited by 36 · see citing works
Self-citationTremblay, M. R., Lin, S., & Poirier, D. (2001) · Steroids · doi:10.1016/s0039-128x(01)00116-7 · Cited by 34 · see citing works
Hormonal Therapy of Prostate Cancer
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“, 1985; Prostate Cancer Triallists’ Collaborative Group, 2000), the affinity of all these com pounds for AR is very low (Labrie et al., 1997; Labrie et al., 1999; Luo et al., 1996; Simard et al., 1997) and leaves an estimated 5–10% of DHT free to continue to stimulate AR and prostate cancer growth (Labrie et al.”
BackgroundSelf-citationLabrie, F. (2014) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.05.012 · Cited by 25 · see citing works
Self-citationProspects for the treatment of endocrine-responsive tumours.
Green, S., & Furr, B. J. A. (1999) · Endocrine Related Cancer · doi:10.1677/erc.0.0060349 · Cited by 25 · see citing works
“There has been considerable controversy over the relative potency of some of the pure antiandrogens, with Luo et al. (1996) championing the superiority of flutamide.”
BackgroundDaily dosing with flutamide or casodex exerts maximal antiandrogenic activity
Luo, S., Martel, C., Chen, C., Labrie, C., Cands, B., Singh, S. M., & Labrie, F. (1997) · Urology · doi:10.1016/s0090-4295(97)00393-2 · Cited by 24 · see citing works
Self-citationHua, Y., Tong, Y.-S., Strock, C., & Johnston, P. (2014) · Assay and drug development technologies · doi:10.1089/adt.2014.594 · Cited by 20 · see citing works
“The FDA approved anti-androgen flutamide is an AR antagonist.(62) Bicalutamide has been reported to induce AR nuclear translocation, DNA binding, and to inhibit AR transcription by recruiting NCoR and SMRT corepressors.”
BackgroundSteroid derivatives as pure antagonists of the androgen receptor
Gauthier, S., Martel, C., & Labrie, F. (2012) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2012.02.006 · Cited by 17 · see citing works
Self-citationNgatcha, B. T., Luu-The, V., & Poirier, D. (2002) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/1475636021000002067 · Cited by 12 · see citing works
Djigoué, G. B., Ngatcha, B. T., Roy, J., & Poirier, D. (2013) · Molecules · doi:10.3390/molecules18010914 · Cited by 10 · see citing works
“Assay for androgen receptor from rat ventral prostate was performed according to the procedure described by Luo and co-workers [35].”
MethodNgatcha, B. T., Laplante, Y., Labrie, F., Luu-The, V., & Poirier, D. (2005) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2005.10.023 · Cited by 9 · see citing works
Self-citationHua, Y., Camarco, D. P., Strock, C. J., et al. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7357-6_13 · Cited by 7 · see citing works
Kolvenbag, G. J. C. M., & Furr, B. J. A. (2009) · Humana Press eBooks · doi:10.1007/978-1-59259-152-7_16 · Cited by 2 · see citing works
Bicalutamide in Advanced Prostate Cancer
Boccardo, F., Kasimis, B. S., Iversen, P., et al. (1998)
Djigoué, G. B. (2014) · Corpus Université Laval (Université Laval)
- Authors
- Luo, S., Martel, C., LeBlanc, G., Candas, B., Singh, S. M., Labrie, C., Simard, J., Belanger, A., & Labrie, F.
- Venue
- Endocrine Related Cancer
- Publisher
- Bioscientifica
- Published
- 1996-09-01
- Volume
- 3
- Issue
- 3
- Pages
- 229-241
- ISSN
- 1351-0088 (ISSN-L)
- 1479-6821
- OpenAlex
- W1983806503
- Cited by
- 23
- References
- 0
- Citations by year
- 2017: 1 · 2014: 3 · 2013: 1 · 2012: 1
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Related Cancer (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- flutamide, bicalutamide, hydroxyflutamide, androgen receptor binding, relative potency, prostate cancer, androgen receptor antagonists, prostate weight, seminal vesicle, dose selection
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