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摘要 : “阿比特龙”(Abiraterone)是设计用来治疗所谓的“去势抵抗性前列腺癌”(对雄性激素拮抗剂无反应的癌症)患者的一种药物。“

“阿比特龙”(Abiraterone)是设计用来治疗所谓的“去势抵抗性前列腺癌”(对雄性激素拮抗剂无反应的癌症)患者的一种药物。“阿比特龙”的作用原理是,通过对名为CYP17A1的酶的抑制来阻断雄性激素的形成,这种酶是睾丸酮和其他雄性激素生物合成中的关键一步。 现在,Nima Sharifi 及同事又有了一个新发现:“阿比特龙”本身在前列腺肿瘤中会被代谢,产生D4A,后者会抑制雄性激素合成通道中的几种酶(也包括CYP17A1在内),还会拮抗雄性激素受体。D4A在动物模型中有更强的抗肿瘤活性,因而可能会导致更有效治疗药物的问世,尤其是鉴于“阿比特龙”的供应还受到某些限制。


Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer


Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer1, 2, 3. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes4, 5. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival6, 7. We hypothesized that abiraterone is converted by an enzyme to the more active Δ4-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone’s clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation—conversion to a more active agent—for abiraterone’s survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.

来源: Nature 浏览次数:0


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