Pharmacology of novel steroidal inhibitors of cytochrome P45017 (17α-hydroxylase/C17–20 lyase)

Barrie, S. E.; Potter, Gerard A.; Goddard, Phyllis M.; Haynes, Benjamin P.; Dowsett, Mitch; Jarman, Michael

doi:10.1016/0960-0760(94)90131-7

Cited by 247 publications

(141 citation statements)

References 15 publications

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“…The data were subjected to exponential growth-curve analysis constrained to share an initial value and to 2-way ANOVA analysis followed by Bonferroni's multiple comparisons test. Significant differences as compared with the vehicle-treated control group (P < 0.05) were detected only for seviteronel at a dose of 100 mg/kg (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”

Section: Methodsmentioning

confidence: 97%

“…Abiraterone is a potent inhibitor of both the hydroxylase and lyase activities of CYP17 (14). In addition to affecting androgen synthesis, inhibition of the hydroxylase activity of CYP17 leads to a reduction in cortisol production and a consequent rise in adrenocorticotrophic hormone (ACTH) and increased mineralocorticoid production, requiring coadministration of glucocorticoids with abiraterone treatment (15).…”

Section: Introductionmentioning

confidence: 99%

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Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Norris

Ellison

Baker

et al. 2017

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Norris

Ellison

Baker

et al. 2017

Journal of Clinical Investigation

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“…In these preclinical studies, there was correlative evidence of inhibition of 17a hydroxylation as shown, for example, by the reduced weight of the ventral prostate (Barrie et al, 1994;Dowsett et al, 1988).…”

mentioning

confidence: 94%

Hormonal impact of the 17α-hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer

et al. 2004

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A series of three dose escalating studies were conducted to investigate the ability of the 17a-hydroxylase/C 17,20 -lyase inhibitor abiraterone acetate, to cause maximum suppression of testosterone synthesis when delivered to castrate and noncastrate males with prostate cancer. Study A was a single dose study in castrate males. Study B was a single dose study in noncastrate males and study C was a multiple dose study in noncastrate males. The drug was given orally in a once-daily dose and blood samples taken to assess pharmacokinetic (PK) parameters and hormone levels in all patients. The study drug was well tolerated with some variability in PKs. Suppression of testosterone levels to o0.14 nmol l À1 was seen in four out of six castrate males treated with a single dose of 500 mg. At 800 mg given days 1 -12 in noncastrate males, target suppression was achieved in three out of three patients, but a two-to threefold increase of Luteinising Hormone (LH) levels in two out of three patients overcame suppression within 3 days. All patients in the multiple dose study developed an abnormal response to a short Synacthen test by day 11, although baseline cortisol levels remained normal. This is the first report of the use of a specific 17a-hydroxylase/ 17,20 -lyase inhibitor in humans. Repeated treatment of men with intact gonadal function with abiraterone acetate at a dose of 800 mg can successfully suppress testosterone levels to the castrate range. However, this level of suppression may not be sustained in all patients due to compensatory hypersecretion of LH. The enhanced testosterone suppression achieved in castrate men merits further clinical study as a second-line hormonal treatment for prostate cancer. Adrenocortical suppression may necessitate concomitant administration of replacement glucocorticoid.

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“…Abiraterone acetate is a selective small molecule inhibitor of cytochrome (CYP) 17, which effectively blocks the production of androgen and estrogen. 68 It was recently tested in a phase I clinical trial and demonstrated a decrease in PSA following treatment in 50% of all men with castration independent prostate cancer. 69,70 In the study, 83% (5/6) with TMPRSS2:ERG fusion prostate cancer had a decrease in PSA following abiraterone treatment.…”

Section: Diagnostic and Clinical Therapy Implicationsmentioning

confidence: 99%

ETS rearrangements in prostate cancer

Rubin¹

2012

Asian J Androl

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Prostate cancer is a clinically and molecularly heterogeneous disease. Understanding the biologic underpinning of prostate cancer is necessary to best determine how biology is associated with the risk of disease progression and how this understanding might provide insight into the development of novel therapeutic approaches. The focus of this review is on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a basic understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease.

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Pharmacology of novel steroidal inhibitors of cytochrome P45017 (17α-hydroxylase/C17–20 lyase)

Cited by 247 publications

References 15 publications

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Hormonal impact of the 17α-hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer

ETS rearrangements in prostate cancer

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