A Phase 1-2 Trial of Diethylstilbestrol Plus Low Dose Warfarin in Advanced Prostate Carcinoma

Klotz, Laurence; McNeill, I. F.; Fleshner, Neil

doi:10.1097/00005392-199901000-00048

Cited by 16 publications

(16 citation statements)

References 10 publications

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“…In this context, estrogen's ability to decrease hypothalamic pituitary stimulation of luteinizing hormone (LH) and folliclestimulating hormone (FSH) production and consequently reduce androgen synthesis made them suitable to be used as a PCa therapy. Unfortunately, estrogen therapy had numerous cardiovascular and thrombotic side effects hindering its clinical use as an alternative to castration (3).…”

Section: Introductionmentioning

confidence: 99%

The Role of Estrogen Receptor β in Prostate Cancer

Christoforou

Christopoulos

Koutsilieris

2014

Mol Med

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Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor β (ERβ) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. ERβ is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the recent experimental findings of ERβ signaling in the prostate.

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Section: Introductionmentioning

confidence: 99%

The Role of Estrogen Receptor β in Prostate Cancer

Christoforou

Christopoulos

Koutsilieris

2014

Mol Med

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“…Although estrogens were previously used for PCa therapy, their efficacy was based on indirect suppression of androgen levels; they also resulted in adverse side effects such as cardiovascular and thromboembolic events (5). It is now known that estrogens acting via ERα mediate aberrant epithelial cell proliferation, prostatic inflammation, and malignancy (6)(7)(8)(9), and ERα antagonists such as Toremifine are in clinical trial for PCa prevention/progression (10).…”

mentioning

confidence: 99%

Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

McPherson

Hussain

Balanathan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

185

147

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Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133 + enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

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“…Interestingly, AIPC cells are more susceptible than androgen-sensitive cells [85,86] . Unfortunately, in a phase-III trial the efficacy of 3 mg DES plus the anticoagulant warfarin in AIPC was only 24% as determined by 1 50% PSA declines, which is low when balanced against the thromboembolic complications [87,88] .…”

Section: Non-traditional Approachesmentioning

confidence: 99%

Rising Prostate-Specific Antigen after Primary Treatment of Prostate Cancer: Sequential Hormone Manipulation

2007

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Objective: To evaluate systematically the current endocrine treatment options for patients with biochemical recurrence after radical prostatectomy or radiation therapy for localized prostate cancer. Methods: Literature search of PubMed documented publications and abstracts from international meetings. Key items included timing and type of salvage hormone therapy, length of its application and handling of side effects. Results: The majority of patients with isolated prostate-specific antigen (PSA) relapse are not candidates for salvage treatment with curative intent. The PSA threshold that triggers initiation of hormonal therapy is debatable and should be based also on pretreatment risk assessment. Intermittent androgen suppression is an emerging concept to circumvent the unresolved controversy of early versus deferred endocrine therapy. Since the tumor load at time of recurrence is low, peripheral androgen blockade with an antiandrogen and a 5α-reductase inhibitor is an acceptable first choice. In case of progression, addition of a LHRH analogue would be the next step. Antiandrogen withdrawal and second-line antiandrogens are clinically of limited value. Conclusions: Biochemical-only progression after definitive treatment in curative intent is different from objective or even symptomatic relapse and allows for sequential hormonal therapy with a variety of compounds.

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A Phase 1-2 Trial of Diethylstilbestrol Plus Low Dose Warfarin in Advanced Prostate Carcinoma

Abstract: The significant thromboembolic toxicity associated with the hypercoagulable state induced by diethylstilbestrol is not reduced by fixed low dose warfarin therapy.

Cited by 16 publications

References 10 publications

The Role of Estrogen Receptor β in Prostate Cancer

The Role of Estrogen Receptor β in Prostate Cancer

Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

Rising Prostate-Specific Antigen after Primary Treatment of Prostate Cancer: Sequential Hormone Manipulation

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