Flutamide: An Antiandrogen for Advanced Prostate Cancer

Goldspiel, Barry R.; Kohler, David R.

doi:10.1177/106002809002400612

Cited by 50 publications

(35 citation statements)

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“…Flutamide is a nonsteroidal androgen receptor antagonist with no agonist activity and is used in the treatment of advanced prostate cancer (30). Its active metabolite, 2-hydroxyflutamide, inhibits the uptake and/or binding of androgens to the androgen receptor (31). Flutamide treatment induces a feedback increase of testosterone associated with a significant augmentation of plasma gonadotropin concentrations (32).…”

Section: Discussionmentioning

confidence: 99%

Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene

Baltatu

Cayla²,

Iliescu³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. A sexual dimorphism in hypertension has been observed in both human and laboratory animal studies. The mechanisms by which male sex hormones regulate cardiovascular homeostasis are still not yet fully understood and represent the subject of this study. The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harboring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with the androgen receptor antagonist Flutamide starting at 4 wk of age. Also, an androgen receptor mutation (testicular feminization mutation [tfm]) was introduced in these rats by crossbreeding male TGR(m-REN2)27 rats with tfm rats. The resulting offspring male rats that contain the tfm mutation are insensitive to androgens.Flutamide treatment or tfm mutation produced a significant attenuation of the development of hypertension. Besides a reduction in cardiac hypertrophy, urinary albumin excretion was blunted and no histologic characteristics of end-organ damage were observed in the kidney after Flutamide treatment. Testosterone levels increased 15-fold after Flutamide treatment and 2.7-fold by the tfm mutation. Also, plasma estrogens and luteinizing and follicle-stimulating hormones were significantly increased. Plasma renin concentrations and activity but not plasma angiotensinogen were reduced. Our results indicate that androgens contribute not only to the development of hypertension, but even more importantly to end-organ damage in TGR(mREN2)27 rats.Men are predisposed to hypertension and cardiovascular diseases more than age-matched, premenopausal women (1). A sexual dimorphism in hypertension has been observed both in human and laboratory animal studies (2). The mechanisms responsible for the gender differences in BP control are not yet clear and continue to be subject of active investigation (3). Evidence is accumulating that androgens may play an important role in gender-associated differences in BP regulation. Several studies have indicated that androgens may mediate hypertension and renal injury (4 -8). However, the mechanisms by which male sex hormones regulate cardiovascular homeostasis are not yet fully understood (3) and represent the subject of this study. There are indications for an interrelation between androgens and the renin-angiotensin system (RAS) (3); therefore, we studied the consequences of androgen receptor blockade on the development of malignant hypertension in transgenic TGR(mREN2)27 rats with overactive RAS (9,10). Androgen receptor inhibition was achieved by treatment with the antagonist Flutamide or by introducing a testicular feminization mutation (tfm) mutation, and BP as well as end-organ damage and RAS and pituitary-gonadal hormones were evaluated. Materials and Methods Rat StrainsMale transgenic heterozygous rats [TGR(mREN2)27] (n ϭ 24 rats) were obtained from the animal facilities of the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Female Long-Evans rats carrying the X-linked rece...

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Section: Discussionmentioning

confidence: 99%

Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene

Baltatu

Cayla²,

Iliescu³

et al. 2002

Journal of the American Society of Nephrology

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“…In treated cells, flutamide is converted into its more active 2-hydroxylflutamide metabolite. 44 Because LNCaP cells respond to I3C or flutamide, these cells were treated with the indicated combinations of 100 M I3C and 5 M flutamide for 48 hours. Treatment with either I3C or flutatmide alone strongly inhibited the incorporation of [ 3 H]thymidine, whereas a combination of both reagents led to more effective growth inhibition, which virtually abolished DNA synthesis (Fig.…”

Section: Effects Of Combinations Of I3c and Flutamide On Lncapmentioning

confidence: 99%

Indole‐3‐carbinol induces a G1 cell cycle arrest and inhibits prostate‐specific antigen production in human LNCaP prostate carcinoma cells

Zhang

Hsu

Kinseth

et al. 2003

Cancer

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BACKGROUNDIndole‐3‐carbinol (I3C), a naturally occurring component of Brassica vegetables, such as cabbage, broccoli, and Brussels sprouts, is a promising anticancer agent for certain reproductive tumor cells. The objective of the current study was to characterize the cell cycle effects of I3C in human prostate carcinoma cells.METHODSThe incorporation of [3H]thymidine and flow cytometry of propidium iodide–stained nuclei were used to monitor I3C‐regulated changes in prostate carcinoma cell proliferation and cell cycle progression. Western blotting was used to document expression changes in cell cycle components and prostate‐specific antigen (PSA) levels. The enzymatic activities of cyclin‐dependent kinases (CDK) were tested by in vitro protein kinase assays using the retinoblastoma protein as a substrate.RESULTSI3C suppressed the growth of LNCaP prostate carcinoma cells in a dose‐dependent manner by inducing a G1 block in cell cycle progression. I3C selectively inhibited the expression of CDK6 protein and transcripts and strongly stimulated the production of the p16 CDK inhibitor. In vitro protein kinase assays revealed the striking inhibition by I3C of immunoprecipitated CDK2 enzymatic activity and the relatively minor down‐regulation of CDK4 enzymatic activity. In LNCaP prostate carcinoma cells, I3C treatment inhibited production of PSA, whereas combinations of I3C and the androgen antagonist flutamide more effectively inhibited DNA synthesis and PSA levels compared with either agent alone.CONCLUSIONSThe results of the current study demonstrated that I3C has a potent antiproliferative effect in LNCaP and other human prostate carcinoma cells. These findings implicate this dietary indole as a potential chemotherapeutic agent for controlling the growth of human prostate carcinoma cells. Cancer 2003. © 2003 American Cancer Society.

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“…13 Flutamide (FLT) is an antiandrogenic agent presently used for monotherapy of androgen-dependent prostate cancer. 14 It acts by inhibiting the uptake and/or binding of dihydrotestosterone to the target cell receptor, thus interfering with androgen action, which requires stability in blood for a sufficient amount of time.…”

Section: Introductionmentioning

confidence: 99%

Novel ionically crosslinked casein nanoparticles for flutamide delivery: formulation, characterization, and in vivo pharmacokinetics

Elzoghby¹,

Helmy²,

Samy³

et al. 2013

IJN

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A novel particulate delivery matrix based on ionically crosslinked casein (CAS) nanoparticles was developed for controlled release of the poorly soluble anticancer drug flutamide (FLT). Nanoparticles were fabricated via oil-in-water emulsification then stabilized by ionic crosslinking of the positively charged CAS molecules below their isoelectric point, with the polyanionic crosslinker sodium tripolyphosphate. With the optimal preparation conditions, the drug loading and incorporation efficiency achieved were 8.73% and 64.55%, respectively. The nanoparticles exhibited a spherical shape with a size below 100 nm and a positive zeta potential (+7.54 to +17.3 mV). FLT was molecularly dispersed inside the nanoparticle protein matrix, as revealed by thermal analysis. The biodegradability of CAS nanoparticles in trypsin solution could be easily modulated by varying the sodium tripolyphosphate crosslinking density. A sustained release of FLT from CAS nanoparticles for up to 4 days was observed, depending on the crosslinking density. After intravenous administration of FLT-CAS nanoparticles into rats, CAS nanoparticles exhibited a longer circulation time and a markedly delayed blood clearance of FLT, with the half-life of FLT extended from 0.88 hours to 14.64 hours, compared with drug cosolvent. The results offer a promising method for tailoring biodegradable, drug-loaded CAS nanoparticles as controlled, long-circulating drug delivery systems of hydrophobic anticancer drugs in aqueous vehicles.

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Flutamide: An Antiandrogen for Advanced Prostate Cancer

Cited by 50 publications

References 43 publications

Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene

Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene

Indole‐3‐carbinol induces a G1 cell cycle arrest and inhibits prostate‐specific antigen production in human LNCaP prostate carcinoma cells

Novel ionically crosslinked casein nanoparticles for flutamide delivery: formulation, characterization, and in vivo pharmacokinetics

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