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Nature:阿比特龙的代谢产物比它的前体具有更强力的抗癌特性

摘要 : 来自克利夫兰诊所(Cleveland Clinic)的研究人员第一次发现,一种获得FDA批准用于治疗转移性前列腺癌的药物——阿比特龙(abiraterone,Abi)的代谢产物比它的前体具有更强力的抗癌特性。这项研究发布在6月1日的《自然》(Nature)杂志上。

 克利夫兰诊所的研究员Nima Sharifi博士发现,在服用这一药物的患者及前列腺癌动物模型体内,甾体抑制剂阿比特龙转化为了更具生理学活性的D4A (Δ4-阿比特龙)。并且,他们发现D4A能够比阿比特龙更有效地杀死侵袭性前列腺癌细胞,表明直接接受D4A治疗或许可以让某些患者受益。

前列腺癌细胞受到雄激素的推动。当前列腺癌扩散时,可以采用雄激素剥夺疗法来切断肿瘤的能量供应。然而,一些侵袭性的转移肿瘤可以对这类治疗产生耐药。在发表于2013年《细胞》(Cell)杂志上的一项里程碑研究中,Sharifi博士描述了一种遗传突变使得前列腺癌细胞生成了自己的激素用作为燃料,使得它们对传统的激素剥夺疗法产生耐药。

阿比特龙是通过阻断对雄激素生成至关重要的一种酶CYP17A1来起作用。Sharifi博士研究小组发现,更具活性的D4A抑制了负责生成雄激素的另外两个酶,并阻断了雄激素受体使得存在的雄激素失活。他们发现12名接受阿比特龙积极治疗的患者血清中均可检测到D4A。D4A的水平因患者而异,这表明个体将阿比特龙代谢为D4A的能力存在差异。

Sharifi说:“还需要更多的研究来揭示确切的相关机制,但我们预测直接用D4A治疗可以延长某些转移性前列腺癌患者的生存期。深入的研究还可能帮助我们开发出一种潜在生物标志物图谱来预测哪些患者将对D4——阿比特龙产生反应。”

前列腺癌是最常见的男性癌症,在美国每年新确诊病例近24万。根据美国癌症协会的数据,在2013年估计有3万人死于前列腺癌。几乎每一个死于前列腺癌的男性都罹患去势抵抗性前列腺癌。

原文标题:Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer

原文摘要: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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