Bilateral Adrenalectomy for Palliative Treatment of Prostatic Cancer

Mahoney, Edward M.; Harrison, J. Hartwell

doi:10.1016/s0022-5347(17)60911-x

Cited by 38 publications

(20 citation statements)

References 8 publications

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“…Inhibition of adrenal androgen production provided the original rationale, in view of the responses obtained by surgical adrenalectomy (Mahoney & Harrison, 1972;Hendry, 1974). Worgul et al (1983) nevertheless questioned whether the decreases in androgen levels with treatment in their patients were necessarily of biological significance, and the same question is posed by our finding that the measured effects on androgen levels were no different between responders and non-responders.…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of these patients, many of them elderly and in poor general condition, is a difficult problem (Lancet, 1980). The response of some patients to cortisone alone (Miller & Hinman, 1954) or to bilateral adrenalectomy (Mahoney & Harrison, 1972;Hendry, 1974) suggests that in some cases the tumour may retain sensitivity to residual adrenal androgens. Aminoglutethimide is an inhibitor of several enzymes involved in adrenal steroid synthesis (Dexter et al, 1967) and in prostaglandin metabolism (Harris et al, 1983c).…”

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confidence: 99%

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Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Ponder¹,

Shearer²,

Pocock³

et al. 1984

Br J Cancer

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Summary Forty patients with metastatic adenocarcinoma of the prostate were evaluated for response to treatment with aminoglutethimide plus cortisone acetate. All had relapsed from or failed to respond to primary endocrine treatment with orchidectomy or stilboestrol. Nineteen patients (48%) showed subjective response, in most cases relief of bone pain. Side effects limited treatment in only 3 patients. We conclude that aminoglutethimide plus cortisone acetate is a useful addition to the treatment available for this difficult group of patients. The mechanism by which this treatment has a beneficial effect remains unclear.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Ponder¹,

Shearer²,

Pocock³

et al. 1984

Br J Cancer

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“…Early studies using bilateral surgical adrenalectomy or hypophysectomy to ablate adrenal androgen production resulted in pain relief in the majority of patients and objective responses in up to 30%, but there was significant morbidity associated with this therapy, and it was replaced by medical adrenalectomy using aminoglutethimide or ketoconazole (56,57). Response rates of about 40% have been reported to aminoglutethimide (usually given with hydrocortisone) in men with androgen-independent prostate cancer (58-60).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer

Stanbrough¹,

Bubley²,

et al. 2006

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Androgen receptor (AR) plays a central role in prostate cancer, and most patients respond to androgen deprivation therapies, but they invariably relapse with a more aggressive prostate cancer that has been termed hormone refractory or androgen independent. To identify proteins that mediate this tumor progression, gene expression in 33 androgenindependent prostate cancer bone marrow metastases versus 22 laser capture-microdissected primary prostate cancers was compared using Affymetrix oligonucleotide microarrays. Multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors (MMP9, CKS2, LRRC15, WNT5A, EZH2, E2F3, SDC1, SKP2, and BIRC5), whereas a candidate tumor suppressor gene (KLF6) was decreased. Consistent with castrate androgen levels, androgen-regulated genes were reduced 2-to 3-fold in the androgen-independent tumors. Nonetheless, they were still major transcripts in these tumors, indicating that there was partial reactivation of AR transcriptional activity. This was associated with increased expression of AR (5.8-fold) and multiple genes mediating androgen metabolism (HSD3B2, AKR1C3, SRD5A1, AKR1C2, AKR1C1, and UGT2B15). The increase in aldo-keto reductase family 1, member C3 (AKR1C3), the prostatic enzyme that reduces adrenal androstenedione to testosterone, was confirmed by real-time reverse transcription-PCR and immunohistochemistry. These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.

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“…Clinical responses to adrenalectomy provided the initial indication that adrenal derived androgens were contributing to CRPC (17). Subsequent studies using ketoconazole, which decreases adrenal androgens by inhibiting the enzyme CYP17A1 that is required for DHEA and androstenedione synthesis, have yielded substantial response rates and further support a role for adrenal androgens in CRPC (18).…”

Section: Introductionmentioning

confidence: 99%

Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors

et al. 2011

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Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1 dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

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Bilateral Adrenalectomy for Palliative Treatment of Prostatic Cancer

Cited by 38 publications

References 8 publications

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer

Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors

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