The Nonsteroidal Effects of Diethylstilbestrol: The Rationale for Androgen Deprivation Therapy Without Estrogen Deprivation in the Treatment of Prostate Cancer

Scherr, Douglas S.; Pitts, W. Reid

doi:10.1097/01.ju.0000077558.48257.3d

Cited by 61 publications

(46 citation statements)

References 63 publications

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“…It is well known that castration and treatment with diethylstilbestrol (DES) result in significant decreases in circulating concentrations of testosterone and DHT (34). To minimize the competitive binding from endogenous androgen, we further compared the biodistribution of 125 I-labeled S-26 in intact rats to that observed in castrated rats and intact rats treated with DES in an attempt to clarify the role of AR mediated uptake in our studies.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging

Yang

Wu²,

Wu³

et al. 2009

Int J Oncol

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Abstract. Knowledge of the presence and extent of disease plays a major role in clinical management of prostate cancer, as it provides meaningful information as to which therapy to choose and who might benefit from this therapy. The wide expression of androgen receptor (AR) in primary and metastatic prostate tumors offers a cellular target for receptormediated imaging of prostate cancer. In our previous study, a non-steroidal AR ligand, S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide] showed promising in vitro pharmacological properties as an AR-mediated imaging agent, with high AR binding affinity and AR specificity. The overall goal of this study was to characterize the in vivo metabolic and biodistribution profile of S-26 in rats. Non-compartmental pharmacokinetic analysis of S-26 in rat plasma showed that clearance (CL), volume of distribution (Vd ss ), and half-life (T 1/2 ) of S-26 were 0.30±0.07 l/h/kg, 1.44±0.33 l/kg, and 4 h, respectively, after intravenous (i.v.) administration. Dose proportionality (1, 10 and 30 mg/kg) studies suggested that the pharmacokinetics of S-26 are dose-independent. The plasma concentrations of all 3 doses were further simultaneously fitted with a two-compartmental model and the results were similar to those obtained from non-compartmental analysis. Biodistribution studies using 125 I-labeled S-26 indicated that it did not specifically target AR-rich tissue (e.g. prostate). A substantial amount of radioactivity recovered from thyroid gland indicated the release of free iodine. In metabolism studies, unchanged S-26 and its metabolites were detected in rat urine and fecal samples. Oxidation, de-iodination, hydrolysis, and sulfate conjugation were the major metabolic pathways of S-26 in rats, with deiodination representing a unique metabolic pathway of S-26 among other selective androgen receptor modulators. In conclusion, the extensive plasma clearance and de-iodination of S-26 likely contribute to its lack of AR tissue selectivity in vivo. Future studies using metabolically stable ligands with less lipophilicity and higher AR binding affinity may represent a promising and rational approach for AR-mediated imaging.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging

Yang

Wu²,

Wu³

et al. 2009

Int J Oncol

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“…However, clinical use has been restricted owing to its adverse side effects, which mainly involve increased heart-vascular complications. Recently, interest in the use of estrogenic therapies for advanced prostate cancer has reemerged, since lower doses of estrogen have proven effective in subpopulations of patients with advanced prostate cancer (5,22,23). Additionally, the administration of estrogens parenterally, which avoids hepatic first-pass metabolism, appears to lower the risk of thromboembolism (24,25).…”

Section: Discussionmentioning

confidence: 99%

Estrogen in combination with 5-azacitidine up-regulates p75NTR expression and induces apoptosis in 22Rv1 prostate cancer cells

Yang²,

Mao³

et al. 2009

Mol Med Rep

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Abstract. Previous studies suggest that the low-affinity neurotrophin receptor p75NTR inhibits the proliferation of human prostate cancer cells, and that estrogen interacts with p75NTR in many tissues. In this study, we exposed 22Rv1 androgen-independent prostate cancer cells to 17-β-estradiol and the DNA demethylating agent 5-azacitidine (5-AzaC) to explore the interactions between estrogen and p75NTR. We found that estrogen induced estrogen receptor (ESR) subtype 2 and p75NTR expression in 22Rv1 cells, and that 5-AzaC further enhanced these effects. Estrogen in combination with 5-AzaC induced cell apoptosis, which was associated with the inhibition of NF-κB translocation to the nucleus. These results provide evidence that the up-regulation of ESR2 and p75NTR by estrogen plus 5-AzaC may be a potential therapeutic strategy for the treatment of androgen-refractory prostate cancer.

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“…Several trials demonstrated a persistence of DES efficiency after a first-line hormonal therapy failure. [2][3][4][5][6][7][8] It has been reported that prostate-specific antigen (PSA) levels decreased by more than half in 21%-86% of patients treated with DES. However, its side effects (e.g., thrombosis and cardiac toxicity) have hindered its use; even at a low dose (1 mg), toxicity was observed in almost 20% of patients.…”

Section: Introductionmentioning

confidence: 99%

“…However, its side effects (e.g., thrombosis and cardiac toxicity) have hindered its use; even at a low dose (1 mg), toxicity was observed in almost 20% of patients. [2][3][4][5][6][7][8][9] Several mechanisms for its action have been suggested, including the inhibition of the hypothalamo-pituitary axis by negative biofeedback, direct testosterone production inhibition by the testis and adrenal glands, and direct cytotoxicity on prostatic cancer cells. This direct effect mechanism is unknown, and identification of the responsible proteins may lead to the development of targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomic determination of diethylstilbestrol action on prostate cancer

Bigot¹,

Mouzat²,

Lebdai³

et al. 2013

Asian J Androl

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Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P,0.01) were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins (.1.3 fold; P,0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P50.006) and HSPB1 (P50.046).

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The Nonsteroidal Effects of Diethylstilbestrol: The Rationale for Androgen Deprivation Therapy Without Estrogen Deprivation in the Treatment of Prostate Cancer

Abstract: The efficacy of 1 mg DES extends well beyond its androgen suppressive effects. Androgen deprivation without estrogen deprivation is a concept that deserves further attention in the urological community.

Cited by 61 publications

References 63 publications

Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging

Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging

Estrogen in combination with 5-azacitidine up-regulates p75NTR expression and induces apoptosis in 22Rv1 prostate cancer cells

Quantitative proteomic determination of diethylstilbestrol action on prostate cancer

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