- Endocrine disruptors affect larval zebrafish behavior: Testing potential mechanisms and comparisons of behavioral sensitivity to alternative biomarkers. [Journal Article]
- ATAquat Toxicol 2017; 193:128-135
- Larval zebrafish (Danio rerio) are a tool for assessing endocrine disruption during early development. Here, we investigated the extent to which a simple light/dark behavioral test at five days post ...
Larval zebrafish (Danio rerio) are a tool for assessing endocrine disruption during early development. Here, we investigated the extent to which a simple light/dark behavioral test at five days post fertilization could compliment current methods within the field. We exposed fertilized embryos to hormones (17β-estradiol, testosterone, dihydrotestosterone, 11-ketotestosterone, thyroxine, triiodothyronine, progesterone, and hydrocortisone) and other relevant compounds (17α ethinylestradiol, bisphenol A, bisphenol S, nonylphenol, flutamide, nilutamide, linuron, drospirenone, potassium perchlorate, mifepristone, and fadrozole) to screen for behavioral effects between 96 and 118h post fertilization (hpf). With the exception of progesterone, all the hormones tested resulted in altered behaviors. However, some inconsistencies were observed regarding the age of the larvae at testing. For example, the xenoestrogens 17α- ethinylestradiol and nonylphenol had behavioral effects at 96hpf, but not at 118hpf. Furthermore, although thyroxine exposure had pronounced effects on behavior, the thyroid disruptor potassium perchlorate did not. Finally, we were unable to demonstrate a role of nuclear receptors following testosterone and 17α- ethinylestradiol exposure, as neither the androgen receptor antagonist flutamide nor the general estrogen receptor inhibitor fulvestrant (ICI) could rescue the observed behavioral effects, respectively. Similarly, molecular markers for androgen and estrogen disruption were upregulated at concentrations below which behavioral effects were observed. These results demonstrate hormones and endocrine disruptors can alter the behavior of larval zebrafish, but the mechanistic pathways remain unclear.
- Cardiovascular disease risk and androgen deprivation therapy in patients with localised prostate cancer: a prospective cohort study. [Journal Article]
- BJBr J Cancer 2017 Oct 10; 117(8):1233-1240
- CONCLUSIONS: In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.
- Review of HPLC and LC-MS/MS assays for the determination of various nonsteroidal anti-androgens used in the treatment of prostate cancer. [Review]
- BCBiomed Chromatogr 2018; 32(1)
- 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 nonst...
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.
- A simple HPLC-UV method for quantification of enzalutamide and its active metabolite N-desmethyl enzalutamide in patients with metastatic castration-resistant prostate cancer. [Journal Article]
- JCJ Chromatogr B Analyt Technol Biomed Life Sci 2017 Jul 15; 1058:102-107
- Enzalutamide is currently approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). To date, a single liquid chromatographic-tandem mass spectroscopy method...
Enzalutamide is currently approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). To date, a single liquid chromatographic-tandem mass spectroscopy method is available to measure plasma enzalutamide concentrations in mCRPC patients. In this work, an accurate and sensitive HPLC-UV method has been developed for the simultaneous determination of enzalutamide and its active metabolite, N-desmethyl enzalutamide in plasma from mCRPC patients. Before precipitation of proteins with acetonitrile, samples were spiked with nilutamide (internal standard). Separation of analytes was achieved under isocratic elution on a C18 Kinetex column. The mobile phase consisted of a mixture of ammonium acetate buffer (pH=4.6, 20mM) and acetonitrile (60:40, v/v), and was delivered at a flow rate of 1.5mL/min throughout a 9-min run. UV detection was performed at 270nm. The method was linear over a concentration range of 0.50-50.0μg/mL for both analytes. Within- and between-day imprecision and accuracy were ≤10% at concentrations 0.75, 5.00, and 50.0μg/mL. This method has been implemented to assay steady-state trough plasma concentrations (n=30) of enzalutamide and N-desmethyl enzalutamide in 16 mCRPC patients. Overall, this HPLC-UV method is well-suited for routine application in clinical laboratories to perform therapeutic drug monitoring of enzalutamide in mCRPC patients.
- Targeting androgen receptor versus targeting androgens to suppress castration resistant prostate cancer. [Journal Article]
- CLCancer Lett 2017 Jul 01; 397:133-143
- Prostate cancer (PCa) is the 2nd leading cause of cancer-related death among men in the United States and its progression is tightly associated with the androgen/androgen receptor (AR) signals. Men c...
Prostate cancer (PCa) is the 2nd leading cause of cancer-related death among men in the United States and its progression is tightly associated with the androgen/androgen receptor (AR) signals. Men castrated before puberty (eunuchs) or men with inherited deficiency of type II 5α-reductase (with failure to convert testosterone to the more potent dihydrotestosterone) (DHT) do not develop PCa. To date, androgen deprivation therapy (ADT) with anti-androgen treatments to reduce or prevent androgens from binding to the AR remains the main therapeutic option for advanced PCa since its discovery by Huggins and Hodges in 1941. Multiple strategies related to surgical/chemical castration with combinations of various anti-androgens, including Cyproterone Acetate, Flutamide, Nilutamide, Bicalutamide (Casodex) and Enzalutamide, as well as some androgen synthesis blockers, including Abiraterone, have been used to control PCa progression. However, patients on ADT with anti-androgen treatment eventually develop resistance, which might be accompanied with the unwanted side effects of enhanced metastasis. New therapeutic approaches via directly targeting the AR with ASC-J9(®), Cisplatin, EPI-001, Niclosamide, and VPC compounds as well as silencing AR with siRNAs or non-coding RNAs have been developed to further suppress PCa at the castration resistant stages.
- Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978). [Journal Article]
- JMJ Med Chem 2016 Dec 08; 59(23):10705-10718
- The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the ...
The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins.
- A highly sensitive and selective electrochemical determination of non-steroidal prostate anti-cancer drug nilutamide based on f-MWCNT in tablet and human blood serum sample. [Journal Article]
- JCJ Colloid Interface Sci 2017 Feb 01; 487:289-296
- A novel electrochemical sensor based on the functionalized multiwalled carbon nanotube (f-MWCNT) was successfully developed for the sensitive and selective determination of non-steroidal prostate ant...
A novel electrochemical sensor based on the functionalized multiwalled carbon nanotube (f-MWCNT) was successfully developed for the sensitive and selective determination of non-steroidal prostate anti-cancer drug nilutamide in tablet and blood serum samples. The f-MWCNT was prepared by the simple reflux method and characterized by the scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Raman spectroscopy, X-ray powder diffraction (XRD) and fourier transform infrared spectroscopy (FT-IR). Interestingly, the f-MWCNT was exhibited a superior electrocatalytic activity towards the anti-cancer drug nilutamide when compared with pristine MWCNT and unmodified electrodes. Besides, the electrochemical sensor was revealed an excellent current response for the determination of nilutamide with wide linear ranges (0.01-21μM and 28-535μM), high sensitivity (11.023 and 1.412μA μM(-1)cm(2)) and very low detection limit (LOD) 0.2nM. The developed electrochemical sensor was showed an excellent selectivity even in the presence of electrochemically active biological substances and nitro aromatic compounds. Moreover, it manifested a good reproducibility and stability. In addition, the f-MWCNT modified glassy carbon electrode (GCE) sensor was successfully applied for the detection of nilutamide in tablet and blood serum sample.
- Androgen Receptor and Beyond, Targeting Androgen Signaling in Castration-Resistant Prostate Cancer. [Review]
- CJCancer J 2016 Sep/Oct; 22(5):326-329
- The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen dep...
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival. Docetaxel was the first agent to demonstrate a survival improvement in this population, and other therapies followed (cabazitaxel, sipuleucel-T and radium-223). Understanding how prostate cancer cells grow in a systemic androgen-deprived environment further changed this clinical landscape. Deciphering what steroidogenic enzymes are overactive and required for testosterone/dihydrotestosterone synthesis has yielded therapies directed toward both adrenal and tumor-derived androgens. All androgens normally act through AR, and this fact remains true in mCRPC. The cancer accomplishes this by overexpressing the receptor (by genomic copy-number gains or RNA amplification), mutating it directly to lose its selectivity for testosterone/dihydrotestosterone, or selecting for splice variants that do not require ligand at all. These resistance mechanisms result in persistent AR-mediated signaling. Through this understanding, drugs targeting non-ligand-binding aspects of AR functioning (e.g., nuclear translocation, cofactor recruitment) have been developed. Finally, how AR interacts with other signaling pathway is being explored, and new combinations of targets to test are being proposed. Multiple compounds remain in various stages of clinical development based on targeting these resistance pathways, and hopefully, they will further the armamentarium for mCRPC. This review visits these mechanisms of resistance, how they are targeted, and remaining challenges in implementing these therapies into clinical practice among the other approved treatments.
- Use of the Hydantoin Directing Group in Ruthenium(II)-Catalyzed C-H Functionalization. [Journal Article]
- JOJ Org Chem 2016 Oct 21; 81(20):10081-10087
- Ruthenium(II)-catalyzed C-H functionalization of N-arylhydantoins is herein described. The biologically relevant hydantoin (imidazolidinedione) heterocycle functions as a weakly coordinating directin...
Ruthenium(II)-catalyzed C-H functionalization of N-arylhydantoins is herein described. The biologically relevant hydantoin (imidazolidinedione) heterocycle functions as a weakly coordinating directing group in a C-H alkenylation reaction. The reaction gave a wide scope of 23 examples with yields up to 94% in the green solvent 2-MeTHF. Functionalization of API nilutamide (antiandrogen) is also reported. The use of the succinimide heterocycle as a directing group is also demonstrated in modest yields.
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- Lung caught in Nilutamide treatment. [Case Reports]
- BCBMJ Case Rep 2016 Sep 06; 2016