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Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy
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Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy
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Journal Article
Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy
2016
Overview
The prostate cancer drug abiraterone can be metabolized into several substances with different effects, and optimization of this process could be helpful for fine-tuning the treatment of prostate cancer.
Manipulating antitumour activity of abiraterone
The anti-androgen prostate cancer drug abiraterone is metabolized in the body to Δ4-abiraterone (D4A), a more potent steroid than abiraterone with structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone. These authors show that D4A is converted in the body to at least six previously unrecognized metabolites with a range of different metabolic effects. In a clinical trial of abiraterone alone, followed by abiraterone plus the 5α-reductase inhibitor dutasteride, production of a downstream tumour-promoting metabolite was blocked and D4A concentrations rose. These findings suggest a previously unappreciated method of clinically fine-tuning abiraterone metabolism to optimize cancer therapy.
Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis
1
,
2
. Abiraterone is metabolized in patients to Δ
4
-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone
3
. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - metabolism
/ 38/39
/ 5-alpha Reductase Inhibitors - pharmacology
/ 5-alpha Reductase Inhibitors - therapeutic use
/ 64/60
/ Abiraterone Acetate - administration & dosage
/ Abiraterone Acetate - metabolism
/ Abiraterone Acetate - therapeutic use
/ Androgen Antagonists - pharmacology
/ Androgen Antagonists - therapeutic use
/ Androstenes - administration & dosage
/ Animals
/ Dutasteride - therapeutic use
/ Enzymes
/ Humanities and Social Sciences
/ Humans
/ letter
/ Male
/ Mice
/ Oxidation-Reduction - drug effects
/ Prostatic Neoplasms - drug therapy
/ Prostatic Neoplasms - metabolism
/ Prostatic Neoplasms, Castration-Resistant - blood
/ Prostatic Neoplasms, Castration-Resistant - drug therapy
/ Prostatic Neoplasms, Castration-Resistant - metabolism
/ Receptors, Androgen - metabolism
/ Science
/ Steroids
