Current status and prospects of androgen depletion therapy for prostate cancer

Department of Urology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Best Practice & Research: Clinical Endocrinology & Metabolism (Impact Factor: 4.6). 05/2008; 22(2):293-302. DOI: 10.1016/j.beem.2008.01.010
Source: PubMed


The old concept of androgen depletion therapy (ADT) for prostate cancer, which had been established on the basis of clinical experiences essentially on the far advanced disease, should be changed. The recent major increase in the diagnosis of localized and locally advanced prostate cancer due to prostate-specific antigen (PSA) screening prompts us to make clear the role of ADT for such an early stage of prostate cancer. Recent literature has proved that combination therapy of castration (medical or surgical) and non-steroidal anti-androgens (maximal androgen blockade, MAB, or combined androgen blockade, CAB) is markedly effective on non-metastatic prostate cancer. It is important to promote basic and clinical research based on the understanding that cure of prostate cancer is almost always possible with ADT if progression to the hormone-independent prostate cancer which accompanies metastatic disease can be avoided.

Full-text preview

Available from:
  • Source
    • "More potent anti-androgens, the key to more successful treatment of prostate cancer While androgen blockade has been known for a long time to be efficacious as first line therapy at all stages of prostate cancer (Akaza, 2008; Huggins and Hodges, 1941; Janknegt et al., 1993; Labrie et al., 2002; Labrie et al., 1985; Namiki et al., 2008), recent data indicate a continuous role of the AR in treatment-resistant metastatic disease (Chen et al., 2004). While the percentage of objective responses in patients with metastatic prostate cancer is higher and the duration of response is longer when CAB is used (Crawford et al., 1989; Jan­ knegt et al., 1993; Labrie et al., 1985), progres­ sion of the disease always occurs if the patients have metastatic disease at start of treatment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to take advantage of this unique property and to always use optimal androgen blockade when hormone therapy is the appropriate treatment. A fundamental observation is that the serum testosterone concentration only reflects the amount of testosterone of testicular origin which is released in the blood from which it reaches all tissues. Recent data show, however, that an approximately equal amount of testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including the prostate, and does not appear in the blood. Consequently, after castration, the 95-97% fall in serum testosterone does not reflect the 40-50% testosterone (testo) and dihydrotestosterone (DHT) made locally in the prostate from DHEA of adrenal origin. In fact, while elimination of testicular androgens by castration alone has never been shown to prolong life in metastatic prostate cancer, combination of castration (surgical or medical with a gonadotropin-releasing hormone (GnRH) agonist) with a pure anti-androgen has been the first treatment shown to prolong life. Most importantly, when applied at the localized stage, the same combined androgen blockade (CAB) can provide long-term control or cure of the disease in more than 90% of cases. Obviously, since prostate cancer usually grows and metastasizes without signs or symptoms, screening with prostate-specific antigen (PSA) is absolutely needed to diagnose prostate cancer at an 'early' stage before metastasis occurs and the cancer becomes non-curable. While the role of androgens was believed to have become non-significant in cancer progressing under any form of androgen blockade, recent data have shown increased expression of the androgen receptor (AR) in treatment-resistant disease with a benefit of further androgen blockade. Since the available anti-androgens have low affinity for AR and cannot block androgen action completely, especially in the presence of increased AR levels, it becomes important to discover more potent and purely antagonistic blockers of AR. The data obtained with compounds under development are promising. While waiting for this (these) new anti-androgen(s), combined treatment with castration and a pure anti-androgen (bicalutamide, flutamide or nilutamide) is the only available and the best scientifically based means of treating prostate cancer by hormone therapy at any stage of the disease with the optimal chance of success and even cure in localized disease.
    Full-text · Article · Dec 2010 · Progress in brain research
  • Source
    • "Androgen (ARs), estrogen (ERs), and progesterone receptors (PRs) are best recognized for their contribution in the morphogenesis of reproductive tissues [2-4]. Conversely, preventing the actions of ARs and ERs has been the major treatment of choice for many years in combating hormone-sensitive prostate and breast cancers respectively [5,6]. Glucocorticoids are clinically invaluable in treating lymphoid cancers and attenuating immune responses [7] while mineralocorticoid agonists are now thought to have significant effects on the heart and vasculature [8,9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Steroid receptors play major roles in the development, differentiation, and homeostasis of normal and malignant tissue. STAMP is a novel coregulator that not only enhances the ability of p160 coactivator family members TIF2 and SRC-1 to increase gene induction by many of the classical steroid receptors but also modulates the potency (or EC50) of agonists and the partial agonist activity of antisteroids. These modulatory activities of STAMP are not limited to gene induction but are also observed for receptor-mediated gene repression. However, a physiological role for STAMP remains unclear. The growth rate of HEK293 cells stably transfected with STAMP plasmid and overexpressing STAMP protein is found to be decreased. We therefore asked whether different STAMP levels might also contribute to the abnormal growth rates of cancer cells. Panels of different stage human cancers were screened for altered levels of STAMP mRNA. Those cancers with the greatest apparent changes in STAMP mRNA were pursued in cultured cancer cell lines. Higher levels of STAMP are shown to have the physiologically relevant function of reducing the growth of HEK293 cells but, unexpectedly, in a steroid-independent manner. STAMP expression was examined in eight human cancer panels. More extensive studies of ovarian cancers suggested the presence of higher levels of STAMP mRNA. Lowering STAMP mRNA levels with siRNAs alters the proliferation of several ovarian cancer tissue culture lines in a cell line-specific manner. This cell line-specific effect of STAMP is not unique and is also seen for the conventional effects of STAMP on glucocorticoid receptor-regulated gene transactivation. This study indicates that a physiological function of STAMP in several settings is to modify cell growth rates in a manner that can be independent of steroid hormones. Studies with eleven tissue culture cell lines of ovarian cancer revealed a cell line-dependent effect of reduced STAMP mRNA on cell growth rates. This cell-line dependency is also seen for STAMP effects on glucocorticoid receptor-mediated transactivation. These preliminary findings suggest that further studies of STAMP in ovarian cancer may yield insight into ovarian cancer proliferation and may be useful in the development of biomarker panels.
    Full-text · Article · Apr 2010 · BMC Cancer
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Complete androgen blockade (CAB) does not prolong overall survival (OS) in patients with castration refractory prostate cancer (CRPC). Although there is variable clinical benefit with second-line hormone manipulation, we do not know which patients might benefit the most. To identify clinical predictors of benefit of complete androgen blockade. We reviewed the records for 54 patients who received treatment with CAB in the setting of disease progression despite castration. We evaluated progression-free survival (PFS) and OS according to PSA at diagnosis, Gleason scores, age, testosterone level, and duration of prior disease control during castration in first line treatment. Among 54 patients who received CAB, the median PFS was 9 months (CI 4.3-13.7) and OS was 36 months (CI 24-48). We did not find an effect of PSA at diagnosis (p = 0.32), Gleason score (p = 0.91), age (p = 0.69) or disease control during castration (p = 0.87) on PFS or OS. Thirty-four patients subsequently received chemotherapy, with a mean OS of 21 months (CI 16.4-25.5, median not reached). Age, Gleason score, PSA at diagnosis and length of disease control with castration did not affect PFS or OS. In the absence of predictors of benefit, CAB should still be considered in CRPC.
    Full-text · Article · Jun 2010 · International braz j urol: official journal of the Brazilian Society of Urology
Show more