As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo, using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects. Mol Cancer Ther; 17(2); 381–92. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

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通过组蛋白去乙酰化酶抑制在体内放射增敏作用，而早期正常组织放射毒性没有增加

随着人口老龄化，越来越多的老年患者需要接受基于放射治疗的盆腔恶性肿瘤治疗，包括肌肉浸润性膀胱癌，因为他们不适合进行大手术。因此，迫切需要为此类患者找到对包括肠和膀胱在内的正常组织毒性最小的放射增敏剂。我们开发了在小动物放射研究平台 (SARRP) 上使用新型放射治疗技术来确定体内肠道和膀胱正常组织毒性严重程度的方法。使用无胸腺裸鼠皮下异种移植物评估帕比司他对体内肿瘤生长延迟的影响。在 CD1 裸鼠中测量异种移植物、血浆和正常组织中的 Panobinostat 浓度水平。CD1-裸小鼠用药物/辐射组合治疗，以使用肠隐窝试验评估小肠中的急性正常组织效应，并在 11 周通过粪便评估和在 12 周通过组织学检查对小肠和大肠的后期效应进行评估。通过 qPCR 评估帕比司他的体外作用，并通过克隆形成测定和蛋白质印迹分析评估帕比司他、TMP195 和 mocetinostat。Panobinostat 导致 RT112 膀胱癌异种移植物的生长延迟，但没有显着增加急性（3.75 天）或 12 周的正常组织辐射毒性。帕比司他的放射增敏作用对缺氧膀胱癌细胞有效，并与 I 类 HDAC 抑制以及 HDAC2 和 MRE11 的蛋白质下调有关。Pan-HDAC 抑制是一种有前途的放射增敏策略，但更具选择性的药物在临床上可能是更有用的放射增敏剂，从而减少全身副作用。摩尔癌症治疗；17（2）；381-92。©2017 AACR。请参阅本 MCT 焦点部分中的所有文章，“放射肿瘤学中的发展治疗学”。