Novel manganese-porphyrin superoxide dismutase-mimetic widens the therapeutic margin in a preclinical head and neck cancer model

Document Type

Article

Abstract

Purpose: 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. Methods and Materials: Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the doseeeffect 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 doseeeffect 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 RTmediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.

Publication Date

1-1-2015

Publication Title

International Journal of Radiation Oncology Biology Physics

ISSN

03603016

E-ISSN

1879355X

Volume

93

Issue

4

First Page

892

Last Page

900

PubMed ID

26530759

Digital Object Identifier (DOI)

10.1016/j.ijrobp.2015.07.2283

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