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Steroid Hormone Receptors Involved in Reproduction: Mechanism of Action
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Paul Robel, Baulieu Etienne-Emile
Cytoproterone acetate has been used the longest, and is the only one available for the treatment of androgen excess syndromes in women. Besides its progestational side effects, it has some slight androgen agonist properties, which are a potential risk for the treatment of prostate cancer. Nowadays, several nonsteroidal antiandrogens, chemically related to anilin, are available; they have a rather low affinity for androgen receptors, even after conversion to active metabolite(s). Large doses must be given, but their major advantage is their pure antagonistic activity.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
LOH is defined as a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels [14 *** ]. It may result in significant deterioration in QoL and adversely affect the functions of multiple organ systems 14***.LOH occurs mainly in the latter half of life, but the prevalence of LOH in the general population is difficult to estimate exactly because the condition is largely underdiagnosed due to its nonspecific presentation. Further, evidence for LOH among male cancer survivors is limited compared to female menopausal symptoms. However, in prostate cancer survivors, where ADT is a widely used treatment modality, decreased libido, erectile dysfunction, and hot flushes are commonly seen AEs 15***. ADT is the standard management for metastatic prostate cancer and commonly used in an adjuvant setting for locally advanced cases. Although transient flare-ups are noticed, the most frequently used agents, Gn-RH analogues, ultimately decrease the serum testosterone levels to castration levels as effectively as bilateral orchiectomy does. The nonsteroidal antiandrogens such as bicalutamide, flutamide, and nilutamide, which are competitive inhibitors of androgen binding, show different AE profiles [16], although the nonsteroidal antiandrogens are frequently used in combination with Gn-RH analogues. The testicular germ cell tumor (TGCT) is a representative curable cancer, with recent cure rates reaching over 80% even in metastatic cases with intensive chemotherapy and surgery. Recently, the results of a large population study have revealed the long-term morbidity of TGCT treatment including nephrotoxicity, neurotoxicity, cardiovascular disease, and secondary malignancy 17***. TGCT patients are known to frequently have hypogonadism before treatment. In addition, as a consequence of multimodality treatment, 12%-16% of TGCT survivors are reported to be classified as having hypogonadal status [18,19]. Although the clinical significance of low-grade hypogonadism in TGTC survivors is less well understood, several studies suggested the association of hypogonadism and development of metabolic syndrome in TGTC survivors [20].
Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021
Published in Expert Opinion on Investigational Drugs, 2022
Zachary J. Brown, D. Brock Hewitt, Timothy M. Pawlik
Multiple unique therapies have been utilized in the treatment of HCC with failed results. In a placebo controlled study of patients with HCC, enzalutamide, a nonsteroidal antiandrogen medication, had no difference in median OS or PFS compared with placebo [103]. Patients who received sorafenib with enzalutamide had an ORR of 10% and a median PFS and OS of 2.9 and 6.7 months, respectively. Therefore, enzalutamide was deemed ineffective and not suitable for future studies [104]. In a phase II study of TRC105, a monoclonal antibody to endolin, in patients with advanced HCC who progressed on sorafenib, TRC105 was well tolerated, one of 27 patients had a PR but the PFS was four months, insufficient to proceed to the second stage of the study [105]. A trial evaluating OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients who progressed on or were intolerant to sorafenib demonstrated insufficient anti-tumor activity with a median TTP of 61 days and DCR of 25–43% [106].
The development of apalutamide for the treatment of prostate cancer
Published in Expert Opinion on Drug Discovery, 2021
Pedro Isaacsson Velho, Pedro Tofani Sant’ Anna, Rommel Fabricio Pereira da Silva, Rafael Dal Ponte Ferreira, Fernando Castilho Venero
Since Charles Huggins and Clarence Hodges discovered that androgen deprivation is an effective treatment for prostate cancer [24], many studies have sought to fully understand this mechanism. However, it was only after the first AR sequence was cloned and mapped to the X chromosome in 1988 by Lubahn et al [25]., there was a significant advance in the use of this knowledge as a therapeutic target for the treatment of prostate cancer. First-generation antiandrogens were steroidal analogs that competitively blocked dihydrotestosterone and testosterone from binding to the AR. The first nonsteroidal antiandrogens developed were cyproterone acetate and diethylstilbestrol, both demonstrating efficacy in castration and for the treatment of advanced prostate cancer [26]. Then, nonsteroidal agents were developed to avoid the progestational effects of steroidal agents, that may have stimulatory activity on the growth of androgen-sensitive cancers [27].
Androgen receptor modulators: a review of recent patents and reports (2012-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Shinya Fujii, Hiroyuki Kagechika
Since AR activation is closely related to aggravation of prostate cancer, AR antagonists are used clinically for the treatment of prostate cancer [18–21]. Cyproterone acetate (7) is a steroidal AR antagonist used in the treatment of androgen-dependent disorders including prostate cancer (Figure 3) [22,23]. Oxendolone (8) is used in the treatment of enlarged prostate in Japan [24]. However, steroidal antagonists exhibit side effects due to cross-activity with other steroid hormone receptors, and therefore various nonsteroidal AR antagonists (nonsteroidal antiandrogens, NSAAs) have been developed. Flutamide (9) is one of the first-generation nonsteroidal AR antagonists; it was discovered in 1967 and has been in clinical use since the 1980s [25,26]. Flutamide (9) has also been a lead compound for the development of various novel nonsteroidal AR antagonists. Two other first-generation NSAAs, the hydantoin derivative nilutamide (10) [27,28] and the sulfone derivative bicalutamide (11) [29,30], have been in clinical use since the 1990s. Bicalutamide (11) is the most potent of the three, having the highest receptor affinity and a superior ADMET profile [31], and is, therefore, the most widely used first-generation NSAA for prostate cancer. Topilutamide (12) is also a first-generation NSAA used for the treatment of pattern hair loss in the Czech Republic and Slovakia [32].