Benefits of Combination Therapy with Flutamide in Patients Relapsing after Castration

Labrie, Fernand; Dupont, André; Giguère, M.; Borsanyi, J.P.; Lacourcière, Yves; Monfette, G.; Emond, Jean; Bergeron, Nicole

doi:10.1111/j.1464-410x.1988.tb13971.x

Cited by 66 publications

(30 citation statements)

References 32 publications

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“…The results obtained will suggest the most suitable hormonal therapy for hormone-refractory metastatic PCa in which specific agonists or antagonists will be recommended or advised against on a patientby-patient basis. For instance, it is known that androgen ablation causes more than a 90% reduction in plasma testosterone level, but only a slight decrease in plasma adrenal androgen levels (46) and the results obtained with mutants AR T877A and AR C685Y show that they were both responsive to androstenedione, an adrenal androgen with which wild-type AR binds with low affinity. Thus blocking the activity of the remaining androstenedione or, even more, reducing its plasma level with glucocorticoids may be worth considering as a more appropriate treatment of PCas that express such mutant ARs.…”

Section: Discussionmentioning

confidence: 99%

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer

Céraline

Erdmann²,

Erbs³

et al. 2003

European Journal of Endocrinology

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Objective: Mutations in the ligand-binding domain of the human androgen receptor (AR) figure among the ways used by prostate adenocarcinoma (PCa) cells to escape androgen dependence. These mutations may broaden the specificity and/or affinity of the AR to other hormones, resulting in inappropriate receptor activation and thus affecting the PCa response to physiological stimuli and hormonal therapies. Design: In order to clarify the impact of these mutations on disease progression and treatment, we have developed a yeast-based functional assay that allows the detection of mutant ARs and the analysis of their transactivation capacities in response to different ligands. Methods: AR cDNA was directly cloned into an expression vector in a yeast strain that carries a reporter gene (ADE2 ) linked to an androgen-dependent promoter. The expression of the ADE2 gene and consequently the yeast cell growth in a selective medium depleted in adenine depends on the specificity of the AR for the ligand added to the medium. Results: By analysing the transactivation capacities of different AR molecules in response to a broad range of steroid and non-steroid ligands, we have demonstrated that this assay can discriminate among wild-type AR, T877A, C685Y and L701H mutant ARs and that at least 1% of mutant ARs could be detected when mutant and wild-type ARs were mixed at the cDNA level. Conclusions:The data presented here show that this simple AR assay is convenient for the routine detection of mutant ARs in PCa and is also suitable to evaluate the antagonist activities of anti-androgen molecules.

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Section: Discussionmentioning

confidence: 99%

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer

Céraline

Erdmann²,

Erbs³

et al. 2003

European Journal of Endocrinology

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“…Multiple clinical studies have shown that intratumoral concentrations of T and 5α-dihydrotestosterone (DHT) sufficient to activate AR-dependent transcription are maintained in CRPC despite suppression of serum T (3)(4)(5)(6). The requirement for the intratumoral generation of androgen ligand is exemplified by frequent and often sustained responses to AR antagonists (7,8), as well as an unprecedented prolongation of survival in chemotherapy-refractory metastatic CRPC conferred by abiraterone acetate, a potent inhibitor of CYP17A1, which is required for the synthesis of adrenal 19-carbon steroid precursors of T and DHT (9).…”

mentioning

confidence: 99%

Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

Chang

Papari-Zareei

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

308

289

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In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.hormonal therapy | 5-alpha-androstanedione | tumor metabolism | abiraterone acetate | hormone resistance

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“…Among androgens it is unique in that both HF and casodex failed to block significantly Adiol-induced AR transactivation in prostate cancer cells. Because castration with or without combination therapy with antiandrogen decreases the serum concentration of Adiol by only 40-50% (20,21), our previous findings suggested that current combined androgen blockade treatment might be insufficient to block Adiol's action in AR-positive prostate cancer. Therefore, we determined whether ADEK inhibited Adiol-induced AR transcription by measuring MMTV-Luc activity.…”

Section: Anti-dht Effect Of Adek On Psa Expression and Cell Proliferamentioning

confidence: 92%

3β-Acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity

Miyamoto

Marwah

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The majority of available antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3β-acetoxyandrost-1,5-diene-17-ethylene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT AR and a mutant AR in prostate cancer cells. ADEK inhibited prostate-specific antigen expression as well as growth in LNCaP prostate cancer cells stimulated by androgen. Importantly, ADEK had only marginal agonist effects, as compared with commonly used antiandrogens such as hydroxyflutamide and bicalutamide, leading to a lower possibility of inducing withdrawal response. Moreover, ADEK could block an adrenal androgen androstenediol-induced AR transactivation that hydroxyflutamide and bicalutamide failed to block. These unique antiandrogenic activities make ADEK a potential therapeutic compound that might be able to inhibit AR-mediated prostate cancer progression. Further in vivo studies might facilitate the development of a better antiandrogen for the treatment of prostate cancer.

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Benefits of Combination Therapy with Flutamide in Patients Relapsing after Castration

Cited by 66 publications

References 32 publications

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer

Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

3β-Acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity

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