Ashcraft Kathleen A, Boss Mary-Keara, Tovmasyan Artak, Roy Choudhury Kingshuk, Fontanella Andrew N, Young Kenneth H, Palmer Gregory M, Birer Samuel R, Landon Chelsea D, Park Won, Das Shiva K, Weitner Tin, Sheng Huaxin, Warner David S, Brizel David M, Spasojevic Ivan, Batinic-Haberle Ines, Dewhirst Mark W
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Department of Molecular Biomedical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, North Carolina.
Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):892-900. doi: 10.1016/j.ijrobp.2015.07.2283. Epub 2015 Jul 29.
To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively.
Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined.
MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors.
MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.
测试一种新型锰卟啉氧化应激调节剂，中-四（N-正丁氧基乙基吡啶-2-基）卟啉锰（MnBuOE），分别在正常组织和肿瘤中对辐射的防护和增敏特性。
用一系列辐射剂量对小鼠口腔黏膜和唾液腺进行处理，同时给予或不给予MnBuOE，以建立黏膜炎和口干症的剂量效应曲线。通过组织蛋白酶活性的活体近红外成像、唾液分泌评估和组织学分析对辐射损伤进行量化。为了评估MnBuOE对肿瘤辐射反应的影响，我们将该药物作为辅助剂用于FaDu异种移植瘤的分次放疗。同样，给予一系列放射治疗（RT）剂量以建立辐射剂量效应曲线。确定有或无MnBuOE时的50%肿瘤控制剂量值和剂量修正因子。
MnBuOE通过减轻放疗介导的黏膜炎、口干症和纤维化来保护正常组织。预防口干症的剂量修正因子为0.77。相比之下，与对照组相比，MnBuOE提高了肿瘤局部控制率。基于50%肿瘤控制剂量值的比值，剂量修正因子为1.3。免疫组织化学显示，经MnBuOE处理的肿瘤表现出大量M1肿瘤相关巨噬细胞的流入，这为其在肿瘤中的放射增敏作用提供了机制上的见解。
MnBuOE通过降低控制肿瘤所需的辐射剂量，同时增加正常组织对放疗介导损伤的抵抗力，拓宽了治疗窗口。这是第一项定量证明单一药物在使肿瘤放射增敏的同时对正常组织具有辐射防护能力大小的研究。
