Current Status of Bilateral Adrenalectomy or Advanced Prostatic Carcinoma

Bhanalaph, T; Varkarakis, M. J.; Murphy, Gerald P.

doi:10.1097/00000658-197401000-00004

Cited by 83 publications

(24 citation statements)

References 14 publications

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“…Our data suggest that secondary hormonal manipulations and pharmacologic inhibitors of androgen biosynthesis derive a component of their activity by directly targeting intratumoral androgen production. This mechanism may explain the relatively high response rates observed in recent clinical studies evaluating specific CYP17A1 inhibitors for castration-resistant prostate cancer when compared with historical rates observed with adrenalectomy (28,(44)(45)(46). Moreover, elevated tumoral androgen levels may underlie the lack of substantial survival benefit associated with the use of AR antagonists, as agents such as bicalutamide have an affinity for the AR which is 30-fold lower than the endogenous ligand (47,48).…”

Section: Intratumoral Androgens In Metastatic Prostate Cancermentioning

confidence: 99%

Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

et al. 2008

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Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment. [Cancer Res 2008;68(11):4447-54]

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Section: Intratumoral Androgens In Metastatic Prostate Cancermentioning

confidence: 99%

Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

et al. 2008

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“…This was based on the finding that enzymes converting testosterone to DHT and dihydroepiandrostenedione to androstenedione were upregulated to a greater extent than the other enzymes in the synthesis pathway (32,33). However, it has also been demonstrated that an adrenalectomy paired with ADT does not limit CaP progression, suggesting limited involvement of adrenal precursors (34,35). Overall, it appears that adrenal precursors are not the only source of ligand for AR activation, and de novo androgen synthesis is likely required to provide sufficient ligand for maintaining this pathway in CRPC cells.…”

Section: De Novo Androgen Synthesis In Castration-resistant Prostate mentioning

confidence: 99%

Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer

Twiddy

León

2010

Pharm Res

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Advanced prostate cancer (CaP) is often treated with androgen deprivation therapy (ADT). Despite high initial success rates of this therapy, recurrence of the cancer in a castration-resistant (CRPC) form is inevitable. It has been demonstrated that, despite the low levels of circulating androgens resulting from ADT, intratumoral androgen levels remain high and androgen receptor activation persists. Recently, it was discovered that de novo androgen synthesis is occurring within the tumor cells themselves, thus providing a potential mechanism for the high endogenous concentrations. A common upstream precursor in this steroidogenic pathway is cholesterol. For many decades, the breakdown of cholesterol homeostasis in cancer has been the focus of research, but this was largely to elucidate its involvement in maintaining membrane integrity and cell signaling. De novo steroidogenesis has provided a new avenue for cholesterol research and reinforces the importance of understanding the mechanisms that lead to the alterations in cholesterol regulation in the progression to CRPC. The findings to date suggest that cholesterol homeostasis is altered to support de novo androgen synthesis and appear to facilitate disease progression. We further propose that a better understanding of the link between cholesterol and de novo androgen synthesis in CaP progression may provide opportunities for novel therapeutic intervention, namely via eliminating sources of the precursor cholesterol. This review summarizes the implications of cholesterol dysregulation in CaP and particularly in the post-ADT castration-resistant state, as well as the potential implementation of novel therapies targeting these cholesterol sources.

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“…In this study 4 patients survived for more than one year, but mean survival was 5 months. A subjective improvement occurred in 10 (Bhanalaph et al 1974). Adrenalectomy, performed concomitantly with orchidectomy, may postpone relapse for a greater period than orchidectomy alone (Reynoso & Murphy 1972).…”

Section: Hormone Receptorsmentioning

confidence: 99%

Hormonal Aspects of Prostatic Cancer: A Review

Waxman

1985

J R Soc Med

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Current Status of Bilateral Adrenalectomy or Advanced Prostatic Carcinoma

Cited by 83 publications

References 14 publications

Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer

Hormonal Aspects of Prostatic Cancer: A Review

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