Clinical Progress with a New
Antiandrogen, Casodex™
(Bicalutamide)

Blackledge, George

doi:10.1159/000473847

Cited by 24 publications

(15 citation statements)

References 11 publications

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“…The EC 50 for testosterone stimulation was increased 19-fold (EC 50 = 3.4 nM) and 100-fold (EC 50 = 18 nM) in the presence of vinclozolin and bicalutamide, respectively. These findings are consistent with earlier reports that these anti-androgens are competitive inhibitors of androgen binding (Blackledge, 1996;McIntyre et al, 2000;Molina-Molina et al, 2006). EC 50 values of 0.86 nM, 2.5 nM and 45 nM were respectively determined for the three anti-androgens, when combined with MAA (Fig.…”

Section: Combination Of Maa With Ar Antagonistssupporting

confidence: 92%

Interactions of methoxyacetic acid with androgen receptor

Bagchi

Hurst

Waxman

2009

Toxicology and Applied Pharmacology

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Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC 50 for androgen responsiveness, partially alleviating the antagonistic effect of the antiandrogens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by ∼90%. De-regulation of these genes may alter androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.

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Section: Combination Of Maa With Ar Antagonistssupporting

confidence: 92%

Interactions of methoxyacetic acid with androgen receptor

Bagchi

Hurst

Waxman

2009

Toxicology and Applied Pharmacology

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“…However, it was found to be less eective than castration, likely owing to the remaining tumor T, not present after castration [11]. Bicalutamide is a nonsteroidal antiandrogen, approved for use in combination therapy, with surgical or medical castration, for advanced prostate cancer [2,3]. The compound is also under investigation as primary monotherapy in patients with advanced disease and as adjuvant therapy in patients with early stage disease [38].…”

Section: Discussionmentioning

confidence: 99%

Combined treatment of Dunning R3327 rat prostatic tumor with the 5α-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide

Zaccheo

Giudici

Panzeri

et al. 2000

Cancer Chemother Pharmacol

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“…Flutamide was the first antiandrogen approved for use in management of advanced PCa by the late 1970s/early 1980s [57][58][59]. Bicalutamide was developed thereafter and found to be significantly more potent than flutamide with a much improved side effect profile, making it the preferred antiandrogen by the mid-1990s [60,61]. Nilutamide was developed around the same time and was shown to be relatively well tolerated as well [62].…”

Section: Ar Mutation and Splice Variantsmentioning

confidence: 99%