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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
This agent has a unique dual mechanism of action, acting as both an androgen receptor antagonist and an inhibitor of CYP17A1, an enzyme required for the biosynthesis of androgens. In 2014 the company announced positive interim results from a Phase 2 study (i.e., ARMOR2), with data showing clinically meaningful reductions in PSA levels. This led to Phase III clinical trials (i.e., ARMOR3-SV) in AR-V7-expressing metastatic castration-resistant prostate cancer patients, comparing galeterone to enzalutamide. However, the trial was discontinued in 2016 when a Data Monitoring Committee determined that clinical endpoints were unlikely to be met. In 2018, it was announced that the agent would continue to be developed through a collaboration between Educational & Scientific LLC (ESL) and the University of Maryland Ventures.
Environmental toxicants on Leydig cell function
Published in C. Yan Cheng, Spermatogenesis, 2018
Leping Ye, Xiaoheng Li, Xiaomin Chen, Qingquan Lian, Ren-Shan Ge
BPA is androgen receptor antagonist because it binds to the human androgen receptor, blocking dihydrotestosterone-mediated androgen receptor transcription activity134,135 with a similar potency as the androgen receptor antagonist flutamide.134,135 Androgens have been shown to critical for Leydig cell development, as shown by the evidence of lower expression levels of CYP17A1 and 17β-HSD3 in the androgen receptor insensitive or knockout rats and mice.138–140
Reproductive System and Mammary Gland
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Justin D. Vidal, Charles E. Wood, Karyn Colman, Katharine M. Whitney, Dianne M. Creasy
Loss of estrogen (or antagonism of the estrogen receptor) may lead to atrophy of the mammary gland, resulting in a decrease of glandular tissue and a reduction in the size of the epithelium lining these structures (Figure 20.42). Mammary gland atrophy has been reported in intact male and/or female rodents treated with potent anti-estrogens such as fulvestrant (ICI 182,780), EM-800, and tamoxifen (Chan et al. 2001; Kennel et al. 2003; Luo et al. 1998). The androgen receptor antagonist flutamide has been shown to induce atrophy of the mammary gland in male rats (Toyoda et al. 2000). Furthermore, it has been suggested that any compound decreasing circulating testosterone might induce atrophy of the mammary gland in the male rat, though this has not been demonstrated experimentally (Creasy 2008b; Lucas et al. 2007; Rudmann et al. 2005). Atrophy of the mammary gland in intact female dogs or NHPs as a result of xenobiotic treatment is not common and may be difficult to assess in the context of a routine general toxicology study.
Clinical characteristics, treatment pattern, and medical costs associated with metastatic castration-resistant prostate cancer in Chinese tertiary care hospital settings
Published in Journal of Medical Economics, 2019
Zhaoxin Qian, Yinhuai Wang, Zhengyan Tang, Da Ren, Zhao Wang, Wendong Chen, Zhihong Li
Among the 70 patients receiving the first treatment episode, hormone therapy, chemotherapy, and BSC accounted for 75.7%, 21.4%, and 2.9%, respectively. The combination of androgen receptor antagonist and luteinizing hormone-releasing hormone (LHRH) agonists was the most used hormone therapy (66.0%). Docetaxel was contained in all chemotherapies, and the most used chemotherapy was the combination of docetaxel and prednisone (46.7%). Other chemotherapies were the combination of docetaxel and androgen receptor antagonist and/or LHRH agonists. The distribution of medications used in the hormone therapy indicated that bicalutamide was ranked as the most utilized medication (71.7%), followed by goserelin (60.4%) and leuprolide (24.5%). Among the 19 patients receiving the second treatment episode, seven patients received hormone therapy and 12 received chemotherapy. Three patients received the third treatment episode. Table 2 summarizes the treatment pattern associated with the three treatment episodes.
Disposition of tris(4-chlorophenyl)methanol and tris(4-chlorophenyl)methane in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral and intravenous administration
Published in Xenobiotica, 2019
Natasha R. Catlin, Suramya Waidyanatha, Sherry R. Black, James M. Mathews, Rodney W. Snyder, Purvi R. Patel, Scott L. Watson, Timothy R. Fennell
A lowest observable adverse effect level of 10 ppm (equivalent to 1.2 mg/kg/day) was established from a four-week dietary exposure to 1–100 ppm TCMPOH. In this study, increased spleen and liver weights and increased Phase-I and II enzyme activities in both male and female Sprague Dawley rats were reported (Foster et al., 1999; Poon et al., 1997). Some reproductive effects were reported in this same study, with decreases in serum follicle stimulating hormone levels in the male rats, but not other hormone levels (Foster et al., 1999). No in vivo data was available for TCPME toxicity. Potential reproductive effects have been indicated in vitro, where TCPME and TCPMOH inhibited the binding of 17β-estradiol to human estrogen receptor (Lascombe et al., 2000), and TCPMOH was a human androgen receptor antagonist (Körner et al., 2004; Schrader & Cooke, 2002). The application of TCPMOH in vitro to human sperm resulted in alterations of sperm motility, vitality, and acrosome reaction (Pflieger‐Bruss et al., 2006).
Cancer epigenetics and the potential of epigenetic drugs for treating solid tumors
Published in Expert Review of Anticancer Therapy, 2019
Zhenghui Liu, Yingxue Gao, Xiong Li
The progression of many cancers depends on aberrant hormone metabolism or the mutation of hormone receptors, for example the mutation of estrogen/estrogen receptor in breast cancer and androgen/androgen receptor in prostate cancer. Hormone antagonists or inhibitors of hormone receptors have become the first-in-class therapeutics for these cancer types. However, cancer patients inevitably develop drug resistance after treatment and epigenetic changes have been identified as a key element for drug resistance. Epigenetic drugs may, therefore, overcome cancer resistance to hormonal drugs. Vorinostat and Bicalutamide, an androgen receptor antagonist, had a synergistic effect on cell proliferation and apoptosis induction in prostate cancer cell lines. In a phase II clinical trial, the combination of these two drugs followed by radical prostatectomy decreased the tumor size of primary prostate cancer [99,100]. A triple combination of TSA, Bicalutamide and Finasteride (a 5α-reductase inhibitor) targeting the androgen pathway had synergistic effects inducing prostate cancer cell apoptosis [101]. Azacytidine plus TSA and Diarylpropionitrile (DPN, a highly potent ERβ agonist) displayed strong anticancer effects, inducing apoptosis and decreasing proliferation in prostate cancer cells, along with downregulation of Cyclin D1 and VEGF [94].