Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model

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• 作者：Kathleen A. Ashcraft ; PhD^&lowast ; ; Mary-Keara Boss ; DVM^&dagger ; ; Artak Tovmasyan ; PhD^&lowast ; ; Kingshuk Roy Choudhury ; PhD^&Dagger ; ; Andrew N. Fontanella ; PhD^§ ; ; Kenneth H. Young ; BS^&lowast ; ; Gregory M. Palmer ; PhD^&lowast ; ; Samuel R. Birer ; BS^&lowast ; ; Chelsea D. Landon ; PhD^&lowast ; ; Won Park ; MD^&lowast ; ; Shiva K. Das ; PhD^‖ ; Tin Weitner ; PhD^&lowast ; ; Huaxin Sheng ; MD^¶ ; ; David S. Warner ; MD^¶ ; ; David M. Brizel ; MD^&lowast ; ; ^# ; Ivan Spasojevic ; PhD^&lowast ; &lowast ; ; Ines Batinic-Haberle ; PhD^&lowast ; ; Mark W. Dewhirst ; DVM ; PhD^&lowast ; ; ^&Dagger ; ; ^{mark.dewhirst@duke.edu" class="auth_mail" title="E-mail the corresponding author}
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：93
• 期：4
• 页码：892-900
• 全文大小：1331 K

文摘

To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) m>meso-m>tetrakis(m>Nm>-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively.

Methods and Materials

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.

Results

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.

Conclusions

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.