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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Nilutamide (NilandronTM, AnandronTM) was discovered and patented by Roussel-UCLAF in 1977 (Figure 8.35) and was the second NSAA to be approved, being introduced into clinical use in France in 1987. It was not available in the US until 1996. Nilutamide has been used in prostate cancer in combination with a GnRH analog but is not approved as a monotherapy. It is also used to prevent tumor flare at the start of GnRH analog therapy. Nilutamide has been mainly superseded in the clinic by NSAAs with improved efficacy, tolerability, and safety profiles such as bicalutamide and enzalutamide, and is now rarely used. It is still obtainable in the US (marketed by Aventis under the trade name NilandronTM) and some other countries (e.g., AnandronTM in Canada) where it is mainly used for prostate cancer patients who are intolerant to flutamide. In the UK, it is not recommended for use in the NHS by NICE. It has also been studied as a component of feminizing hormone therapy for transgender women, and to treat seborrhea and acne in women.
Pneumonitis induced by non-cytotoxic agents
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Umair A Gauhar, J Allen D Cooper
Nilutamide is a non-steroidal, synthetic antiandrogen used in the treatment of metastatic prostate cancer. Pfitzenmeyer et al. described eight patients with metastatic prostate cancer who were on nilutamide therapy and developed respiratory symptoms, hypoxaemia with bilateral infiltrates on chest imaging.112 Pulmonary function testing showed restrictive parameters in six patients. Average duration of therapy was 113 days and mean cumulative exposure was 21.8 g. Six patients underwent bronchoscopy with BAL revealing lymphocytosis in four and neutrophilia in two patients. Nilutamide therapy was stopped in seven patients and decreased from 300 mg to 150 mg per day in one. Two patients were also given corticosteroids. All patients showed improvement in symptoms, pulmonary functions and P aO2. This study estimated an incidence of 1 per cent for nilutamide-induced interstitial pneumonitis. Akoun et al. demonstrated BAL lymphocytosis with a reversed CD4/CD8 ratio and the release of leucocyte inhibition factor by sensitized peripheral blood T-cells in the presence of nilutamide, suggesting that the underlying mechanism for the lung damage may be cell-mediated hypersensitivity reaction.113 Simultaneous lung and liver toxicity that improved on discontinuation of the drug has been reported.114 The congener bicalutamide may also cause ILD.115
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
The first-generation nonsteroidal antiandrogens flutamide and nilutamide, and the second-generation nonsteroidal antiandrogen bicalutamide, selectively inhibit the AR, and have similar potency. Both first- and second-generation antiandrogens can eventually develop agonist rather than antagonist activity due to stimulation of the AR, causing rising in PSA. The advantage of bicalutamide compared to with first-generation antiandrogens is the longer half-life (7 days, compared with 6–8 hours of flutamide [28] and 2 days of nilutamide [29]), permitting once daily dosing. Third-generation antiandrogens are an AR antagonists that inhibit AR translocation to the cell nucleus, recruitment of AR cofactors, and AR binding to DNA [21,23]. This class of antiandrogens, represented by enzalutamide, apalutamide, and darolutamide, has higher affinity and selectivity for the AR compared to second-generation antiandrogens. Importantly, these compounds did not exhibit agonistic activity to AR when used in an AR saturated environment in contrast to their first- and second-generation predecessors [23]. All these third-generation antiandrogens are approved in different settings of the treatment of prostate cancer, both in metastatic and nonmetastatic disease. Because abiraterone acetate and ketoconazole are CYP17 inhibitors, decreasing androgen levels but with no relevant antiandrogen effect on AR, we did not review it here.
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
Prostate cancer is the second most common cancer in men worldwide, with more than 1.2 million new cases diagnosed and more than 350,000 deaths in 2018 [24]. For patients who elect to treat their cancer, hormone therapy is commonly prescribed in both first-line and salvage settings and is composed of therapies that lower the levels of androgens produced by the body, and anti-androgens that function as AR antagonists. First-generation AR antagonists such as bicalutamide, flutamide, and nilutamide established AR blockade as an efficacious clinical strategy for prostate cancer therapy [25]. However, these drugs do not block AR signaling under all conditions and can even act as AR agonists under conditions of elevated AR protein expression common in aggressive prostate cancers. Second-generation AR antagonists enzalutamide 1, apalutamide 2, and darolutamide 3Figure 2 are AR antagonists with greater AR selectivity, binding affinity, and clinical efficacy compared to first-generation drugs, and are pure AR antagonists which do not exhibit a switch to AR agonism except under certain AR mutation conditions.
Increased Risk of Hypertension with Enzalutamide in Prostate Cancer: A Meta-Analysis
Published in Cancer Investigation, 2019
Hormonal therapy has been a cornerstone for treatment of advanced prostate cancer for decades. In addition to traditional agents including leuteinizing hormone-releasing hormone (LHRH) agonists/antagonists for medical castration and first generation anti-androgens (bicalutamide, flutamide, and nilutamide), new agents including abiraterone, enzalutamide, apalutamide, and darolutamide were FDA approved for prostate cancer treatment progressed after androgen deprivation treatment (1–3). These agents have been shown to be effective in treating advanced prostate cancer and prolonging overall survival or metastasis-free survival of these patients in randomized clinical trials (4–7). Enzalutamide has been approved for the treatment of castration-resistant non-metastatic prostate cancer as well as metastatic prostate cancer, and in the process of pending approval for castration-sensitive metastatic prostate cancer (6). Abiraterone and enzalutamide have distinctly different mechanisms of action. While abiraterone reduces the synthesis of testosterone by inhibiting cytochrome P450 (CYP17) enzymes (8–10), enzalutamide targets androgen receptor and its signaling pathway by competitively binding to the ligand-binding domain of the androgen receptor, thereby inhibits androgen-receptor translocation to the cell nucleus, recruitment of androgen-receptor cofactors and androgen-receptor binding to DNA (11).