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1.
World J Urol ; 41(8): 2051-2062, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35596809

RESUMO

PURPOSE: The aim of this study was to investigate the oncologic efficacy of combining docetaxel with androgen deprivation therapy (ADT) versus nonsteroidal antiandrogen (NSAA) with ADT in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with focus on the effect of sequential therapy in a real-world clinical practice setting. METHODS: The records of 382 patients who harbored high-volume mHSPC, based on the CHAARTED criteria, and had received ADT with either docetaxel (n = 92) or NSAA (bicalutamide) (n = 290) were retrospectively analyzed. The cohorts were matched by one-to-one propensity scores based on patient demographics. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), and time to second-line progression (PFS2) were compared. 2nd-line PFS defined as the time from CRPC diagnosis to progression after second-line therapy was also compared. RESULTS: After matching, a total of 170 patients were retained: 85 patients treated with docetaxel + ADT and 85 patients treated with NSAA + ADT. The median OS and CSS for docetaxel + ADT versus NSAA + ADT were not reached (NR) vs. 49 months (p = 0.02) and NR vs. 55 months (p = 0.02), respectively. Median time to CRPC and PFS2 in patients treated with docetaxel + ADT was significantly longer compared to those treated with NSAA (22 vs. 12 months; p = 0.003 and, NR vs. 28 months; p < 0.001, respectively). There was no significant difference in 2nd-line PFS between the two groups. CONCLUSIONS: Our analysis suggested that ADT with docetaxel significantly prolonged OS and CSS owing to a better time to CRPC and PFS2 in comparison to NSAA + ADT in high-volume mHSPC.


Assuntos
Drogas Antiandrogênicas não Esteroides , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Docetaxel/uso terapêutico , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/uso terapêutico , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Androgênios/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Pontuação de Propensão , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
2.
Rev Med Liege ; 77(10): 609-615, 2022 Oct.
Artigo em Francês | MEDLINE | ID: mdl-36226398

RESUMO

Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of treatment for advanced prostate cancer. In the metastatic setting, although ADT is initially effective, castration-resistant disease eventually develops in almost all men with prostate cancer. Since 2015, the addition of docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide with docetaxel to ADT has been shown to improve overall survival (OS) of patients starting ADT for metastatic disease. Castration resistance occurs when disease progresses despite testosterone in the castrate range most commonly with or, more rarely, without detectable metastases. The addition of next-generation antiandrogens to ADT has been shown to improve OS in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) identified by a PSA doubling time (DT) ? 10 months. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor without agonist activity. When added to ADT apalutamide has been shown to improve OS by 35 % in patients starting ADT for metastatic prostate cancer both in patients with upfront metastatic disease or after previous treatment with curative intent. Similarly apalutamide has been shown to provide a 14-month OS improvement in patients with nmCRPC and short PSA DT. These OS benefits were obtained at no cost in terms of quality of life. Apalutamide is given orally once a day and is well tolerated. The most common side effects are fatigue, rash, hypertension and hot flushes. Potential interactions with concomitant medication should be taken into account.


La privation androgénique, chimique au moyen d'agonistes ou d'antagonistes de la LHRH, ou chirurgicale par orchidectomie, est un élément essentiel du traitement du cancer de la prostate avancé. Chez les patients métastatiques, son efficacité est cependant transitoire et une progression survient invariablement. Depuis 2015, une amélioration de la survie des patients métastatiques devant débuter une privation androgénique a été démontrée par l'instauration précoce soit d'une chimiothérapie par docétaxel, soit d'une hormonothérapie de nouvelle génération telle que l'abiratérone, l'enzalutamide, l'apalutamide, voire un traitement combinant docétaxel et darolutamide. Lorsque les patients progressent en dépit de la privation androgénique, on les dit résistants à la castration, le plus souvent en présence de métastases mais parfois en l'absence de lésion secondaire identifiable. Dans le cas des patients non métastatiques résistant à la castration à risque élevé d'évolution défavorable en raison d'un temps de doublement du PSA ? 10 mois, on a également démontré que l'ajout d'un anti-androgène de nouvelle génération améliorait la survie globale des patients. L'apalutamide, ou Erleada®, est un inhibiteur sélectif du récepteur aux androgènes, sans activité agoniste, administré par voie orale. Son instauration, en même temps que la privation androgénique, permet de réduire de 35 % la mortalité des patients métastatiques d'emblée ou secondairement après un traitement initial à visée curative. De même, l'apalutamide permet d'augmenter de 14 mois la survie des patients non métastatiques résistant à la castration à risque élevé d'évolution défavorable. Ces améliorations de la survie globale ont été obtenues sans détérioration de la qualité de vie. L'Erleada® est globalement bien toléré, et facile à administrer, s'agissant d'une prise orale unique quotidienne. La fatigue, la toxicité cutanée souvent modérée, l'hypertension artérielle et les bouffées de chaleur sont les effets secondaires les plus fréquents. Il convient également d'être attentif aux interactions médicamenteuses potentielles.


Assuntos
Drogas Antiandrogênicas não Esteroides , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Androgênios/uso terapêutico , Docetaxel/uso terapêutico , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Ligantes , Masculino , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Antígeno Prostático Específico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Qualidade de Vida , Receptores Androgênicos/uso terapêutico , Testosterona/uso terapêutico , Tioidantoínas
3.
Prostate ; 82(1): 3-12, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559410

RESUMO

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.


Assuntos
Acetato de Abiraterona , Anilidas , Neoplasias Hepáticas , Nitrilas , Prednisolona , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Compostos de Tosil , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/efeitos adversos , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Pesquisa Comparativa da Efetividade , Humanos , Japão/epidemiologia , Testes de Função Hepática/métodos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Drogas Antiandrogênicas não Esteroides/administração & dosagem , Drogas Antiandrogênicas não Esteroides/efeitos adversos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prognóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Neoplasias de Próstata Resistentes à Castração/etiologia , Estudos Retrospectivos , Medição de Risco/métodos , Compostos de Tosil/administração & dosagem , Compostos de Tosil/efeitos adversos
4.
Nat Rev Urol ; 18(7): 433-442, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34002069

RESUMO

Metastatic prostate cancer is associated with considerable morbidity and mortality. Standard treatment for non-metastatic prostate cancer, to prevent metastatic progression, is androgen deprivation therapy (ADT); however, many patients will eventually develop castration-resistant prostate cancer (CRPC), which can prove challenging to treat. Between the stages of non-metastatic androgen-sensitive disease and metastatic CRPC is an intermediate disease state that has been termed non-metastatic CRPC (nmCRPC), which is a heterogeneous, man-made disease stage that occurs after a patient who has no radiological evidence of metastasis shows evidence of cancer progression even after ADT. Awareness of nmCRPC has risen owing to an increased use of ADT and its eventual failure. Men with nmCRPC are at a high risk of progression to mCRPC, with historically few options to halt this process. However, in the past two decades, multiple therapies have been investigated for the treatment of nmCRPC, including endothelin receptor antagonists and bone-targeted therapies, but none has changed the standard of care. In the past decade, the efficacy of androgen receptor pathway-targeting modalities has been investigated. Three novel nonsteroidal antiandrogen agents for treating high-risk nmCRPC have been investigated; the PROSPER, SPARTAN and ARAMIS trials were phase III, randomized, placebo-controlled clinical trials that investigated the efficacy and safety of enzalutamide, apalutamide and darolutamide, respectively. All three therapeutics showed statistically significant improvements in metastasis-free survival, progression to antineoplastic therapy was lengthened and at final analysis, overall survival was significantly improved. The comparative efficacy and safety of all three agents has not yet been investigated in a comprehensive clinical trial, but approval of these medications by the FDA and other regulatory agencies means that providers now have three effective therapeutic options to augment ADT for patients with nmCRPC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/uso terapêutico , Tioidantoínas/uso terapêutico , Adenocarcinoma/patologia , Humanos , Masculino , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida
5.
Int J Mol Sci ; 21(15)2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32759847

RESUMO

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(N-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.


Assuntos
Androgênios/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/genética , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Cumarínicos/farmacologia , Flutamida/análogos & derivados , Flutamida/química , Flutamida/farmacologia , Humanos , Masculino , Estrutura Molecular , Mutação , Drogas Antiandrogênicas não Esteroides/química , Drogas Antiandrogênicas não Esteroides/farmacologia , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/efeitos dos fármacos
6.
World J Urol ; 38(3): 601-611, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30830274

RESUMO

PURPOSE: Standard androgen deprivation therapy (ADT) can be initiated early at the time of diagnosis in asymptomatic castration-sensitive advanced prostate cancer. This definition has recently been expanded to also include an early combined treatment with standard ADT and new antihormonal drugs. We aimed to present the best available evidence for the timing of initiation of ADT monotherapy and combined treatments in castration-sensitive/-resistant prostate cancer. METHODS: For this narrative review, we searched Cochrane reviews in the Cochrane Library, systematic reviews and randomized controlled trials in MEDLINE, phase III and ongoing trials in ClinicalTrials.gov and screened the reference lists to extract articles of interest. One author screened the references which were finally included after assessing their relevance through discussion with other experts in the field. RESULTS: The identified references were grouped by medication (standard ADT, androgen biosynthesis inhibitor, androgen receptor antagonists or combined therapies) and tumor stage (castration sensitive or resistant). The evidence was narratively summarized and discussed in the context of the current therapeutic landscape. CONCLUSIONS: Early standard ADT can reduce symptoms of disease progression and may extend progression-free and overall survival. The patient should be well informed about the higher rates of treatment-related side effects. Deferring standard ADT might be indicated only for well-informed or unfit patients. Early standard ADT is increasingly combined with new antihormonal drugs in castration-sensitive metastatic prostate cancer to gain additional survival and quality of life benefits. Combined treatment at the time of development of castration-resistant disease is well established.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores da Síntese de Esteroides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias da Próstata/tratamento farmacológico , Fatores de Tempo
7.
Rev Recent Clin Trials ; 15(1): 34-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31692438

RESUMO

BACKGROUND: Prostate cancer (PCa) is the sixth primary cause of cancer death. However, conflicts are present about the efficacy and safety of Non-steroidal anti-androgens (NSAA) for its treatment. The aim of this study was to assess the efficacy and safety of NSAAs versus any comparator for the treatment of advanced or metastatic PCa (mPCa). METHODS: MEDLINE and the Cochrane Library were searched. References of included studies and clinicaltrials.gov were also searched for relevant studies. Only English language studies after 1990 were considered for review. Randomized controlled trials (RCTs) examining the efficacy and safety of NSAAs as compared with any other comparator including surgery or chemotherapy in mPCa patients were included. The outcomes include efficacy, safety and the tolerability of the treatment. The Cochrane Risk of Bias Assessment Tool was used for quality assessment. Two authors were independently involved in the selection, extraction and quality assessment of included studies and disagreements were resolved by discussion or by consulting a third reviewer. RESULTS: Fifty-eight out of 1307 non-duplicate RCTs with 29154 patients were considered for the review. NSAA showed significantly better progression-free survival [PFS] (Hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46-0.78; P=0.0001), time to distant metastasis or death [TTD] (HR, 0.80; 95% CI 0.73-0.91; P<0.0001), objective response (Odds ratio [OR], 1.64; 95% CI 1.06-2.54; P=0.03) and clinical benefits (OR, 1.33; 95% CI 1.08-1.63; P=0.006) as compared to the control group. There was no significant difference observed between the groups in terms of overall survival (HR, 0.95; 95%CI, 0.87-1.03; P=0.18) and time to progression (HR, 0.93; 95% CI 0.77-1.11; P=0.43). Treatment-related adverse events were more with the NSAA group, but the discontinuation due to lack of efficacy reason was 43% significantly lesser than the control group in patients with mPCa. Rest of the outcomes were appeared to be non-significant. CONCLUSION: Treatment with NSAA was appeared to be better efficacious with respect to PFS, TTD, and response rate with considerable adverse events when compared to the control group in patients with metastatic PCa.


Assuntos
Drogas Antiandrogênicas não Esteroides/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Asian J Androl ; 20(6): 545-550, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30106011

RESUMO

Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen (NSAA) is still widely used in treating metastatic castration-resistant prostate cancer (mCRPC), especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate (Abi) remains uncertain. In the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA (from bicalutamide to flutamide) before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival (PSA-PFS, 5.5 vs 5.6 months, P = 0.967), radiographic progression-free survival (rPFS, 12.8 vs 13.4 months, P = 0.508), overall survival (OS, not reached vs 30.6 months, P = 0.606), or PSA-response rate (71.4% [15/21] vs 60.6% [40/66], P = 0.370). This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors' decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.


Assuntos
Acetato de Abiraterona/uso terapêutico , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anilidas/uso terapêutico , Intervalo Livre de Doença , Feminino , Flutamida/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Masculino , Nitrilas/uso terapêutico , Antígeno Prostático Específico/análise , Estudos Retrospectivos , Análise de Sobrevida , Compostos de Tosil/uso terapêutico , Resultado do Tratamento
10.
Biomed Chromatogr ; 32(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28636139

RESUMO

Prostate cancer is the most common cancer and one of the leading causes of cancer deaths in men. One of the commonly used approaches to treat metastatic prostate cancer was via first-generation nonsteroidal anti-androgens (NSAAs), namely flutamide, nilutamide, bicalutamide and topilutamide. Most prostate cancer patients who are initially responsive develop the most aggressive form of disease called castration-resistant prostate cancer. Second-generation NSAA receptor antagonists (enzalutamide, apalutamide and darolutamide) are emerging as additional new options to treat castration-resistant prostate cancer. The objective of this work was to review the literature on the bioanalytical methods for the quantification of first- and second-generation NSAA inhibitors in clinical (human plasma) and preclinical (mouse plasma, rat plasma, urine and tissue homogenates etc.) studies along with relevant case studies for some chosen drugs. Based on the review, it was concluded that the published methodologies using either HPLC or LC-MS/MS are well suited for the quantification of NSAA inhibitors in various biological fluids to delineate pharmacokinetic data.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Drogas Antiandrogênicas não Esteroides/análise , Neoplasias da Próstata/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Animais , Humanos , Masculino , Drogas Antiandrogênicas não Esteroides/farmacocinética , Neoplasias da Próstata/metabolismo
11.
Arch Toxicol ; 91(12): 3961-3989, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28879601

RESUMO

The current investigation examines whether combined exposure to three anti-androgens (flutamide, prochloraz, vinclozolin) result in interference with endocrine homeostasis when applied at very low dose levels, and whether the results of combined exposure are more pronounced than to the individual compounds. A pre-post-natal in vivo study design was chosen with more parameters than regulatory testing protocols require (additional endpoints addressing hormone levels, morphology and histopathological examinations). Dose levels were chosen to represent the lowest observed adverse effect level (LOAEL), the no observed adverse effect level (NOAEL), and the acceptable daily intake for each individual substance. Anti-androgenic changes were observable at the effect level (LOAEL) but not at lower exposures. Nipple/areola counts appeared to be a sensitive measure of effect, in addition to male sex organ weights at sexual maturation, and finally gross findings. The results indicate the absence of evidence for effects at low or very low dose levels. No (adverse) effects were seen at the NOAEL dose. A non-monotonic dose-response relationship was not evident. Combined exposure at LOAEL level resulted in enhanced responses for anogenital index, number of areolas/nipples, delayed preputial separation and reduced ventral prostate weight in comparison to the individual compounds.


Assuntos
Relação Dose-Resposta a Droga , Flutamida/administração & dosagem , Imidazóis/administração & dosagem , Drogas Antiandrogênicas não Esteroides/administração & dosagem , Oxazóis/administração & dosagem , Animais , Ciclo Estral/fisiologia , Feminino , Flutamida/toxicidade , Imidazóis/toxicidade , Masculino , Mamilos/patologia , Nível de Efeito Adverso não Observado , Drogas Antiandrogênicas não Esteroides/toxicidade , Oxazóis/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Espermatozoides/citologia , Testosterona/metabolismo
12.
Urol Oncol ; 35(9): 576, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28789926

RESUMO

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater antitumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5ß-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumor-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5ß-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.


Assuntos
Androstenos/uso terapêutico , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Androstenos/administração & dosagem , Androstenos/farmacologia , Humanos , Masculino , Drogas Antiandrogênicas não Esteroides/administração & dosagem , Drogas Antiandrogênicas não Esteroides/farmacologia , Neoplasias da Próstata/patologia
13.
Hum Reprod ; 32(7): 1465-1473, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28482050

RESUMO

STUDY QUESTION: Are bisphenol A (BPA) and BPA analogs (BPA-A) safe for male human reproductive function? SUMMARY ANSWER: The endocrine function of human testes explants [assessed by measuring testosterone and insulin-like factor 3 (INSL3)] was impacted by exposure of the human adult testis explants to BPA/BPA-A. WHAT IS KNOWN ALREADY: The few epidemiologic studies performed suggest that bisphenols have potential endocrine disruptive properties, but they did not identify clear and direct patterns of endocrine disruption. STUDY DESIGN, SIZE, DURATION: Adult human testis explants in culture were exposed to BPA and the analogs bisphenol F (BPF), bisphenol S (BPS), bisphenol E (BPE), bisphenol B (BPB) and bisphenol A diglycidyl ether (BADGE) at 10-9-10-5 M for 24 or 48 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human adult testes were obtained from prostate cancer patients who had no hormone therapy, or from multiorgan donors. After ex vivo exposure to the investigated bisphenols, the measured outcomes were related to histopathology (gross morphology and germ cell viability determined by anti-caspase three immunohistochemistry), and the levels of testosterone, INSL3 and inhibin B were measured using immunoassays. The levels of mRNA encoding key enzymes of bisphenol biotransformation were investigated by quantitative PCR: UGT2B15 UDP (glucuronosyltransferase two family, polypeptide B15), GUSB (glucuronidase beta), SULT1A1 and 3 (sulfotransferase family 1 A member 1 and 3) and STS (steroid sulfatase). MAIN RESULTS AND THE ROLE OF CHANCE: A significant dose-dependent inhibition was found between testosterone levels measured in the culture medium and concentrations of BPA (P = 0.00778 at 24 h and P = 0.0291 at 48 h), BPE (P = 0.039) and BPF (P = 0.00663). The observed BPA and BPA-A-induced inhibition of testosterone production varied according to duration of exposure and BPA/BPA-A concentrations. BPA (10-9 M; P < 0.05), BPB (10-9 M; P < 0.05), BPS (10-9 and 10-8 M; P < 0.05) and BADGE (10-5 M; P < 0.05) increased Leydig cell INSL3 production. By contrast, BPE dose dependently inhibited INSL3 (P = 0.0372). Conversely, Sertoli cell function (inhibin B) and germ cell viability were not significantly affected by either bisphenols. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Environmental compounds cannot be deliberately administered to men, justifying the use of an ex vivo approach. A relatively low number of testes samples were available for analysis (n = 3, except for testosterone secretion with n = 5). The active concentrations of BPA and BPA-A used in the study were higher than those found in human biological fluids. WIDER IMPLICATIONS OF THE FINDINGS: Under our experimental conditions, direct exposure to BPA or BPA-A can result in endocrine disturbance in the adult human testis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Inserm (Institut National de la Santé et de la Recherche Médicale), EHESP-School of Public Health, University of Rennes1, by grants from the Agence Nationale de la Recherche (ANR; grant#ANR-13-CESA-0012-03 NEWPLAST) and Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES; grant#EST-2010/2/046 (BPATESTIS)). All authors declare they have no current or potential competing financial interests.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Insulina/agonistas , Drogas Antiandrogênicas não Esteroides/toxicidade , Fenóis/toxicidade , Proteínas/agonistas , Testículo/efeitos dos fármacos , Testosterona/antagonistas & inibidores , Adulto , Apoptose/efeitos dos fármacos , Arilsulfotransferase/genética , Arilsulfotransferase/metabolismo , Compostos Benzidrílicos/química , Disruptores Endócrinos/química , Compostos de Epóxi/toxicidade , Glucuronidase/genética , Glucuronidase/metabolismo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Insulina/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Drogas Antiandrogênicas não Esteroides/química , Fenóis/química , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Reprodutibilidade dos Testes , Células de Sertoli/citologia , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Esteril-Sulfatase/genética , Esteril-Sulfatase/metabolismo , Sulfonas/toxicidade , Testículo/citologia , Testículo/metabolismo , Testosterona/metabolismo , Técnicas de Cultura de Tecidos
14.
Biochem Pharmacol ; 139: 3-14, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28411115

RESUMO

Marine sponges have consistently been the richest source of new marine natural products with unprecedented chemical scaffolds and potent biological activities that have been reported in the chemical literature since the early 1970s. During the last 40years, chemists in the Andersen laboratory at UBC, in collaboration with biologists, have discovered many novel bioactive sponge natural products. Four experimental drug candidates for treatment of inflammation and cancer, that were inspired by members of this sponge natural product collection, have progressed to phase I/II/III clinical trials. This review recounts the scientific stories behind the discovery and development of these four drug candidates; IPL576,092, HTI-286 (Taltobulin), EPI-506 (Ralaniten acetate), and AQX-1125.


Assuntos
Organismos Aquáticos/química , Produtos Biológicos/química , Desenho de Fármacos , Descoberta de Drogas , Drogas em Investigação/química , Poríferos/química , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/química , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Antimitóticos/efeitos adversos , Antimitóticos/química , Antimitóticos/farmacologia , Antimitóticos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Produtos Biológicos/isolamento & purificação , Cicloexanóis/efeitos adversos , Cicloexanóis/química , Cicloexanóis/uso terapêutico , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Glicerol/análogos & derivados , Glicerol/farmacologia , Glicerol/uso terapêutico , Humanos , Indanos/efeitos adversos , Indanos/química , Indanos/uso terapêutico , Drogas Antiandrogênicas não Esteroides/efeitos adversos , Drogas Antiandrogênicas não Esteroides/química , Drogas Antiandrogênicas não Esteroides/farmacologia , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Oligopeptídeos/efeitos adversos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Pró-Fármacos/efeitos adversos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Pirrolidinonas/efeitos adversos , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/uso terapêutico
15.
J Med Chem ; 60(7): 3082-3093, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28272894

RESUMO

Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.


Assuntos
Drogas Antiandrogênicas não Esteroides/química , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Triazóis/química , Triazóis/uso terapêutico , Animais , Linhagem Celular Tumoral , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Modelos Moleculares , Drogas Antiandrogênicas não Esteroides/farmacologia , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , Triazóis/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-28109972

RESUMO

Urea-based herbicides are applied in agriculture to control broadleaf and grassy weeds, acting to either inhibit photosynthesis at photosystem II (phenylureas) or to inhibit acetolactate synthase acetohydroxyacid synthase (sulfonylureas). While there are different chemical formulas for urea-based herbicides, the phenylureas are a widely used class in North America and have been detected in aquatic environments due to agricultural run-off. Here, we summarize the current state of the literature, synthesizing data on phenylureas and their biological effects in two non-target animals, fish and amphibians, with a primary focus on diuron and linuron. In fish, although the acutely lethal effects of diuron in early life stages appear to be >1mg/L, recent studies measuring sub-lethal behavioural and developmental endpoints suggest that diuron causes adverse effects at lower concentrations (i.e. <0.1mg/L). Considerably less toxicity data exist for amphibians, and this is a knowledge gap in the literature. In terms of sub-lethal effects and mode of action (MOA), linuron is well documented to have anti-androgenic effects in vertebrates, including fish. However, there are other MOAs that are not adequately assessed in toxicology studies. In order to identify additional potential MOAs, we conducted in silico analyses for linuron and diuron that were based upon transcriptome studies and chemical structure-function relationships (i.e. ToxCast™, Prediction of Activity Spectra of Substances). Based upon these analyses, we suggest that steroid biosynthesis, cholesterol metabolism and pregnane X receptor activation are common targets, and offer some new endpoints for future investigations of phenylurea herbicides in non-target animals.


Assuntos
Anfíbios/fisiologia , Disruptores Endócrinos/toxicidade , Peixes/fisiologia , Herbicidas/toxicidade , Resíduos de Praguicidas/toxicidade , Compostos de Fenilureia/toxicidade , Poluentes Químicos da Água/toxicidade , Anfíbios/embriologia , Anfíbios/crescimento & desenvolvimento , Animais , Hibridização Genômica Comparativa , Biologia Computacional , Diurona/química , Diurona/toxicidade , Disruptores Endócrinos/química , Peixes/embriologia , Peixes/crescimento & desenvolvimento , Herbicidas/química , Linurona/química , Linurona/toxicidade , Estrutura Molecular , Drogas Antiandrogênicas não Esteroides/química , Drogas Antiandrogênicas não Esteroides/toxicidade , Concentração Osmolar , Resíduos de Praguicidas/química , Compostos de Fenilureia/química , Relação Estrutura-Atividade , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/química
17.
Arch Toxicol ; 91(1): 143-162, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26914364

RESUMO

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the "expected NOEL" was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels.


Assuntos
Ecotoxicologia/métodos , Fungicidas Industriais/toxicidade , Imidazóis/toxicidade , Lactação , Modelos Químicos , Drogas Antiandrogênicas não Esteroides/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Administração Oral , Animais , Relação Dose-Resposta a Droga , Ecotoxicologia/legislação & jurisprudência , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/sangue , Disruptores Endócrinos/toxicidade , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/induzido quimicamente , Reabsorção do Feto/sangue , Reabsorção do Feto/induzido quimicamente , Fungicidas Industriais/sangue , Fungicidas Industriais/normas , Imidazóis/administração & dosagem , Imidazóis/sangue , Masculino , Drogas Antiandrogênicas não Esteroides/administração & dosagem , Drogas Antiandrogênicas não Esteroides/sangue , Gravidez , Puberdade Tardia/sangue , Puberdade Tardia/induzido quimicamente , Distribuição Aleatória , Ratos Wistar , Toxicocinética , Anormalidades Urogenitais/sangue , Anormalidades Urogenitais/induzido quimicamente , Aumento de Peso/efeitos dos fármacos
18.
J Am Soc Hypertens ; 10(8): 671-82, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27372428

RESUMO

Diabetes predicts cardiovascular disease (CVD); some drugs are effective for CVD prevention but increase the risk of diabetes. In a systematic review and meta-analysis of placebo-controlled trials, we assessed if spironolactone, a mineralocorticoid receptor antagonist, affected glycemic control. We searched PubMed using ("spironolactone" or "aldactone") and trial and ("glucose" or "diabetes" or "insulin" or "insulin resistance") until January 4, 2016. In total, 18 eligible trials were identified; 10 on fasting glucose, 8 on hemoglobin A1c (HbA1c), 7 on homeostatic model assessment (HOMA)-insulin resistance (IR), and 8 on insulin. Spironolactone increased HbA1c (0.16%, 95% confidence interval 0.02 to 0.30) but had no clear effect on fasting glucose, HOMA-IR, and insulin. A mechanistic randomized controlled trial in people with and without diabetes might provide insight concerning these pleiotropic effects on diabetes and CVD relevant to prevention of both diseases.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus/induzido quimicamente , Diuréticos/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Drogas Antiandrogênicas não Esteroides/efeitos adversos , Espironolactona/efeitos adversos , Glicemia/metabolismo , Diuréticos/uso terapêutico , Jejum/fisiologia , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipoglicemiantes/análise , Insulina/análise , Resistência à Insulina/fisiologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Espironolactona/uso terapêutico
19.
World J Biol Psychiatry ; 17(1): 2-38, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26595752

RESUMO

The primary aim of these guidelines was to evaluate the role of pharmacological agents in the treatment of adolescents with paraphilic disorders who are also sexual offenders or at-risk of sexual offending. Psychotherapeutic and psychosocial treatments were also reviewed. Adolescents with paraphilic disorders specifically present a different therapeutic challenge as compared to adults. In part, the challenge relates to adolescents being in various stages of puberty and development, which may limit the use of certain pharmacological agents due to their potential side effects. In addition, most of the published treatment programmes have used cognitive behavioural interventions, family therapies and psychoeducational interventions. Psychological treatment is predicated in adolescents on the notion that sexually deviant behaviour can be controlled by the offender, and that more adaptive behaviours can be learned. The main purposes of these guidelines are to improve the quality of care and to aid physicians in their clinical decisions. These guidelines brought together different expert views and involved an extensive literature research. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for efficacy, safety, tolerability and feasibility. An algorithm is proposed for the treatment of paraphilic disorders in adolescent sexual offenders or those who are at risk.


Assuntos
Terapia Cognitivo-Comportamental , Drogas Antiandrogênicas não Esteroides/uso terapêutico , Transtornos Parafílicos/diagnóstico , Transtornos Parafílicos/terapia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Delitos Sexuais/psicologia , Adolescente , Psiquiatria Biológica , Humanos , Medição de Risco , Fatores de Risco , Sociedades Médicas
20.
Prostate ; 75(9): 897-906, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25728532

RESUMO

BACKGROUND: In the United States, half of men with prostate cancer harbor the androgen-regulated gene fusion TMPRSS2:ERG. We hypothesized that men with TMPRSS2:ERG positive tumors are more responsive to androgen deprivation therapy (ADT). METHODS: We studied a cohort of 239 men with prostate cancer from the Physicians' Health Study and Health Professionals Follow-up Study who received ADT during their disease course. Fusion status was assessed on available tumor tissue by immunohistochemistry for ERG protein expression. We used Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for assessment of prostate cancer-specific mortality after ADT initiation. RESULTS: Roughly half of the men had stage T3 or higher tumors at diagnosis and 39% had Gleason 8-10 tumors. During an average follow up of 10.2 years, 42 men died from prostate cancer. There was a non-significant inverse association between positive fusion status and time to death from prostate cancer after ADT (multivariable HR: 0.76; 95% CI: 0.40-1.45). Harboring the TMPRSS2:ERG fusion was associated with a statistically significant lower risk of prostate cancer mortality among men who were treated with orchiectomy (multivariable HR: 0.13; 95% CI: 0.03-0.62), based on 15 events. CONCLUSIONS: Our results, combined with those from earlier studies, provide suggestive evidence that men with TMPRSS2:ERG positive tumors may have longer prostate cancer survival after ADT. Larger cohorts are needed for more robust results and to assess whether men with tumors harboring the fusion benefit from treatment with ADT in the (neo) adjuvant or metastatic setting specifically.


Assuntos
Drogas Antiandrogênicas não Esteroides/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Idoso , Estudos de Coortes , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/terapia , Proteínas de Fusão Oncogênica/metabolismo , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inquéritos e Questionários , Análise de Sobrevida
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