Casodex™ (Bicalutamide):
Overview of a New Antiandrogen
Developed for the Treatment of
Prostate Cancer

Blackledge, George; Cockshott, I. D.; Furr, B. J. A.

doi:10.1159/000474547

Cited by 26 publications

(11 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[46,49] Bicalutamide is a nonsteroidal antiandrogen with a low binding affinity to AR and a prolonged half-life. [51,52] The relative potency of hydoxyflutamide and bicalutamide in target tissues are a subject of debate, and contrasting results were obtained in different experimental systems. [53,54] Because bicalutamide does not efficiently penetrate the blood-brain barrier, the drug is excluded from central sites of androgen-negative feedback.…”

Section: Androgen Receptor Mutations and Antagonist/agonist Balance Omentioning

confidence: 99%

Androgen Receptor Mutations in Carcinoma of the Prostate

Čulig

Klocker

Bartsch

et al. 2001

American Journal of PharmacoGenomics

View full text Add to dashboard Cite

Endocrine therapy for advanced prostate cancer involves androgen ablation (orchiectomy or application of luteinizing hormone releasing hormone analogs) and/or blockade of the androgen receptor (AR) with either steroidal (cyproterone acetate) or nonsteroidal (hydroxyflutamide, bicalutamide and nilutamide) antiandrogens. These antagonists prevent androgen-induced conformational change and activation of the AR. During long term androgen ablation, the AR adapts to an environment with low androgen concentrations and becomes hypersensitive to low concentrations of androgens, either alone or in combination with various cellular regulators. Bicalutamide can switch from antagonist to agonist during long-term androgen withdrawal, as shown in prostate cancer LNCaP cells. AR point mutations were detected in metastatic lesions from human prostate cancer more frequently than in primary tumors. Although functional characterization of only some mutant AR detected in prostate cancer tissue has been performed, data available suggest that they are activated by dihydrotestosterone, its precursors and metabolites, synthetic androgens, estrogenic and progestagenic steroids and hydroxyflutamide. A direct association between AR mutations and endocrine withdrawal syndrome has been investigated in only one study thus far. There is no evidence at present that activation of any of the mutant AR genes detected in prostate cancer is enhanced in the presence of a nonsteroidal AR stimulator. Coactivators of the AR are proteins that associate with the receptor, possess histone acetylase activity and facilitate AR activation. The coregulatory proteins ARA70 and ARA160 differentially affected the activity of the mutated AR Glu(231)-->Gly, which was discovered in a mouse authochthonous prostate tumor. ARA70 enhanced receptor activation by both androgen and estradiol, whereas ARA160 augmented only androgen-induced AR activity. Novel experimental therapies that down-regulate AR expression have been developed; they include the application of ribozymes and antisense oligonucleotides.

show abstract

Section: Androgen Receptor Mutations and Antagonist/agonist Balance Omentioning

confidence: 99%

Androgen Receptor Mutations in Carcinoma of the Prostate

Čulig

Klocker

Bartsch

et al. 2001

American Journal of PharmacoGenomics

View full text Add to dashboard Cite

show abstract

“…Subsequent studies reported bicalutamide-induced transaminitis and/or hyperbilirubinemia [3,7,11,12]. These elevations are typically transient and patients remain asymptomatic [3].…”

Section: Discussionmentioning

confidence: 99%

Bicalutamide-induced hepatotoxicity: A rare adverse effect

et al. 2014

View full text Add to dashboard Cite

Patient: Male, 81Final Diagnosis: Prostate cancerSymptoms: Anorexia • dark urine • joundice • letargyMedication: CasodexClinical Procedure: —Specialty: OncologyObjective:Adverse events of drug therapyBackground:Bicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature.Case Report:An 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days.Conclusions:While rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.

show abstract

“…Playing a critical role in PCa development and progression, the AR has emerged as a primary therapeutic target. Different strategies have been developed to block the production or action of androgens that provide growth and survival signals to prostate cells [7][8][9][10][11][12][13][14]. The currently used AR antagonists, such as flutamide, bicalutamide, nilutamide and enzalutamide (MDV3100), act by binding to the androgen binding site (ABS) of the AR, resulting in conformational changes that prevent its activation [7,11,14].…”

Section: Introductionmentioning

confidence: 99%

“…Different strategies have been developed to block the production or action of androgens that provide growth and survival signals to prostate cells [7][8][9][10][11][12][13][14]. The currently used AR antagonists, such as flutamide, bicalutamide, nilutamide and enzalutamide (MDV3100), act by binding to the androgen binding site (ABS) of the AR, resulting in conformational changes that prevent its activation [7,11,14]. Although initial responses to AR antagonists are usually favorable and suppression of prostate tumor growth is observed, with time, the diseases transforms and progresses to metastatic CRPC where patients develop resistance to antiandrogen drugs [8,[15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

Biron

Bédard

2016

The Journal of Steroid Biochemistry and Molecular Biology

View full text Add to dashboard Cite

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.

show abstract

Casodex™ (Bicalutamide): Overview of a New Antiandrogen Developed for the Treatment of Prostate Cancer

Cited by 26 publications

References 29 publications

Androgen Receptor Mutations in Carcinoma of the Prostate

Androgen Receptor Mutations in Carcinoma of the Prostate

Bicalutamide-induced hepatotoxicity: A rare adverse effect

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

Contact Info

Product

Resources

About