高剂量的乙氨基与同时抑制CYP2E1具有强烈的抗癌活性,没有肝毒性.
Allyn Bryan1, Pavani Pingali1, Anthony Faber1
1Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.).
The Journal of pharmacology and experimental therapeutics
|November 2, 2023
概括
高剂量的乙氨基 (AAP) 可以通过同时服用皮等CYP2E1抑制剂来安全地进行抗癌作用. 这种策略可以防止肝脏毒性,使剂量升级具有强烈的抗瘤活性.
科学领域:
- 药理学 药理学是指药理学的学科.
- 肝病学 肝病学是一种肝病学.
- 在瘤学瘤学.
背景情况:
- 乙氨基 (AAP) 的新陈代谢包括硫化,葡萄糖化和CYP2E1介导的转化到有毒的NAPQI.
- 抑制CYP2E1是一种管理AAP毒性的策略,其中N-乙半氨酸 (NAC) 和fomepizole具有临床意义.
- 高剂量AAP对抗癌活性的治疗潜力受到剂量依赖性肝毒性限制.
研究的目的:
- 为了研究高剂量AAP与CYP2E1抑制对潜在的抗癌应用的安全性和有效性.
- 评估福梅皮和NAC对AAP诱导的肝毒性的保护作用.
- 评估AAP与毒性减轻剂结合的体外和体内抗瘤活性.
主要方法:
- 小鼠接受了乙氨基 (AAP) 治疗,并与福梅皮 (一种CYP2E1抑制剂) 和N-乙半氨酸 (NAC) 相结合.
- 使用组织学和血清化学来评估肝脏毒性.
- 使用4T1乳腺癌和易斯肺癌瘤模型,包括免疫功能受损的小鼠,对抗癌活性进行了体外和体内评估.
主要成果:
- 福梅皮,有或没有NAC,完全防止了AAP诱导的肝毒性.
- 高剂量的AAP (650 mg/kg) 与NAC/fomepizole救援在体内显示出显著的抗瘤活性.
- 在免疫受损的小鼠中,抗瘤疗效降低了,这表明免疫介导机制.
结论:
- 同时服用CYP2E1抑制剂可以安全地将AAP的剂量升级到强烈抗癌活性所需的水平.
- 这种方法减轻了AAP诱导的肝毒性,为新的癌症治疗策略开辟了道路.
- 高剂量AAP的抗瘤作用至少部分依赖于完整的免疫系统.
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