Combination of Autophagy Selective Therapeutics With Doxil: An Assessment of Pathological Toxicity.
Combination of Autophagy Selective Therapeutics With Doxil: An Assessment of Pathological Toxicity.
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DOI：
10.3389/ftox.2022.937150
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发表时间：
2022
影响因子：
--
通讯作者：
Delaney, Joe R.
中科院分区：
文献类型：
--
作者：
Helke, Kristi L.;Gudi, Radhika R.;Vasu, Chenthamarakshan;Delaney, Joe R.
背景：癌症治疗中靶向药物的联合治疗是一个不断变化的领域，研究平衡副作用与疗效。联合治疗的功效通过合成致死性或通过预防复发性克隆来改善。先前的研究表明，（羟基）氯喹不足以破坏肿瘤中的自噬。因此，需要组合或新型自噬剂。卵巢癌的体内研究表明，氯喹可以与多达四种其他自噬药物联合使用，以抑制卵巢癌的生长。虽然现在已经确定了自噬药物组合的癌症疗效，但尚不清楚在人体试验中可能需要监测哪些毒性。化疗的附加毒性也是未知的。 方法：为了比以前的体重监测研究更深入地解决毒性问题，进行了生化和组织病理学研究。小鼠组用自噬药物治疗2周，有或没有化疗Doxil。末次给药后，对小鼠进行血液生化、白色血细胞标志物和组织病理学检查。 结果如下：本文报告了来自综合血液生化小组、血细胞标志物的流式细胞术测量和组织病理学的数据。虽然Doxil表现出明显的骨髓和免疫毒性，但自噬药物的毒性总体上较低，并且在其潜在毒性的表现方面更具多样性。仅观察到自噬药物与Doxil的微小累加效应。 结论：自噬药物的组合可以考虑用于人类肿瘤学试验中的治疗，可能的副作用由这些小鼠临床前数据监测。
Background: Combination therapy of targeted drugs in cancer treatment is a field in constant flux, with research balancing side effects with efficacy. Efficacy from combination therapy is improved either through synthetic lethality or through prevention of recurrent clones. Previous research has shown (hydroxy-)chloroquine is insufficient to disrupt autophagy in tumors. Hence, either combinations or novel autophagy agents are desired. In vivo studies of ovarian cancer have revealed that chloroquine can be combined with up to four other autophagy drugs to suppress ovarian cancer growth. While cancer efficacy is now established for the autophagy drug combination, it is unclear what toxicities may require monitoring in human trials. Additive toxicity with chemotherapy is also unknown. Methods: To address toxicity in more depth than previous weight-monitoring studies, biochemical and histopathology studies were performed. Mouse groups were treated with autophagy drugs for 2 weeks, with or without the chemotherapy Doxil. After the last dose, mice were processed for blood biochemistry, white blood cell markers, and histopathology. Results: Data from a comprehensive blood biochemistry panel, flow cytometric measurements of blood cell markers, and histopathology are herein reported. While Doxil presented clear bone marrow and immunologic toxicity, autophagy drugs were overall less toxic and more variable in their presentation of potential toxicities. Only minor additive effects of autophagy drugs with Doxil were observed. Conclusion: Combinations of autophagy drugs may be considered for therapy in human oncology trials, with possible side effects to monitor informed by these murine pre-clinical data.
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影响因子：
29
作者：
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通讯作者：
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影响因子：
1.8
作者：
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影响因子：
16.6
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Akbari O
DOI：
10.1161/circimaging.115.003584
发表时间：
2016-12
期刊：
Circulation. Cardiovascular imaging
影响因子：
--
作者：
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通讯作者：
Neilan TG
影响因子：
5.6
作者：
Chude CI;Amaravadi RK
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