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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Flutamide is a low molecular weight (276.21) prodrug which, after absorption, is rapidly α-hydroxylated to its primary active form, hydroxyflutamide (Figure 8.34). This metabolite competes with testosterone and DHT for their binding site on the androgen receptor (AR) in prostate cancer cells. Thus it acts as a “silent” antagonist of the AR in these cells, blocking their growth. Crucially, due to its small size and good distribution throughout the body, hydroxyflutamide has both peripheral and central activity on all androgen target cells.
Endocrine Disruptors and Male Sexual Dysfunction
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Suresh C. Sikka, Muammer Kendirci, Rajesh Naz
Chemicals that can bind to the AR without activating it and simultaneously prevent binding of true androgens are called antiandrogens. Examples of antiandrogens include hydroxyflutamide, the pesticides procymidone [36] and vinclozolin [38], and the DDT metabolite p,p′-DDE [39]. O,p′-DDT has weak estrogenic activity. Estradiol and DES have some affinity for the AR [39, 40]. Therefore, the mechanism by which estrogenic chemicals impair development of the male reproductive system may be via antiandrogenic properties rather than or in addition to activity related to estrogen receptor activation.
Loco-regional drug delivery in oncology: current clinical applications and future translational opportunities
Published in Expert Opinion on Drug Delivery, 2021
Seona M. Rossi, Timothy Murray, Liam McDonough, Helena Kelly
Liproca® Depot (LIDSS Pharma) utilizes a drug-delivery platform known as Nanozolid® for the loco-regional treatment of prostate cancer to deliver 2-hydroxyflutamide for up to 6 months. Nanozolid® is made of granules of compressed calcium sulfate mixed with non-compressed calcium sulfate hemihydrate powder and is rehydrated at point of use to form an injectable paste [103,104]. An initial burst release is observed from the drug content contained in the non-compressed powder, with the granule-encapsulated drug demonstrating prolonged release. Intra-procedural imaging of the loco-regional delivery is facilitated by the radiopaque calcium sulfate [105]. Combined results published from two Phase I/II single-arm interventional clinical trials (NCT00913263 & NCT02341404) (n = 47) demonstrated that treatment was overall well tolerated following intra-prostatic administration of drug-loaded paste. However, the clinical response was variable across the patient population, indicating that further optimization on clinical dosing and distribution of this drug-delivery platform is required to demonstrate true clinical benefit [104]. Based on the efficacy results from these clinical trials a third clinical trial is underway to assess the potential application of Liproca® Depot during active surveillance of individuals at high risk of progression of prostate cancer (NCT03348527).
Reversibility of castration resistance status after Radium-223 dichloride treatment: clinical evidence and review of the literature
Published in International Journal of Radiation Biology, 2019
Maria Ricci, Viviana Frantellizzi, Nadia Bulzonetti, Giuseppe De Vincentis
Base substitutions in the coding sequence of the AR gene are less frequently observed than AR amplifications. Clinically relevant mutations that may result in increased AR transactivation activity occur in the ligand-binding domain region (LBD) (Robinson et al. 2015). Activation of mutant AR by adrenal androgens, progesterone, cortisol and cortisone, β-estradiol, testosterone metabolites, and moreover, the anti-androgens hydroxyflutamide, bicalutamide and enzalutamide has been documented. Thus, base substitutions in the AR can be responsible for a reactivation of the AR-signaling axis, through alternative steroidal and non-steroidal ligands under conditions where DHT is restricted.
An up-to-date evaluation of darolutamide for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Mohamad Moussa, Lazaros Lazarou, Athanasios Dellis, Mohamed Abou Chakra, Athanasios Papatsoris
Darolutamide and its active metabolites have inhibitory concentration (IC) values of 60–100 nmol/L and 5670–7650 nmol/L, respectively, against wild-type AR, when stimulated by an agonist such as R1881. Potentially, darolutamide antagonizes AR F876L, while enzalutamide and apalutamide do not. Additionally, it has potent activity against M896T and M896V as well as mutant AR W741L and AR T877A, which has proven resistance to bicalutamide and hydroxyflutamide [25]. However, a reduction in drug activity was observed during T878A mutation.