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

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 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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.ijrobp.2015.07.2283

Publication Info

Ashcraft, Kathleen A, Mary-Keara Boss, Artak Tovmasyan, Kingshuk Roy Choudhury, Andrew N Fontanella, Kenneth H Young, Gregory M Palmer, Samuel R Birer, et al. (2015). Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model. International journal of radiation oncology, biology, physics, 93(4). pp. 892–900. 10.1016/j.ijrobp.2015.07.2283 Retrieved from https://hdl.handle.net/10161/23266.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Roy Choudhury

Kingshuk Roy Choudhury

Adjunct Associate Professor in the Department of Biostatistics & Bioinformatics

Statistical modelling, data analysis.
Analysis of multiple observer studies.
Analysis of complex data.
Modelling tumor growth. Translation in drug discovery.
Statistical analysis of images: cellular and medical imaging.
Statistics of shape, structure and spatial arrangement.

Palmer

Gregory M. Palmer

Professor of Radiation Oncology

Greg Palmer obtained his B.S. in Biomedical Engineering from Marquette University in 2000, after which he obtained his Ph.D. in BME from the University of Wisconsin, Madison. He is currently an Associate Professor in the Department of Radiation Oncology, Cancer Biology Division at Duke University Medical Center. His primary research focus has been identifying and exploiting the changes in absorption, scattering, and fluorescence properties of tissue associated with cancer progression and therapeutic response. To this end he has implemented a model-based approach for extracting absorber and scatterer properties from diffuse reflectance and fluorescence measurements. More recently he has developed quantitative imaging methodologies for intravital microscopy to characterize tumor functional and molecular response to radiation and chemotherapy. His awards have included the Jack Fowler Award from the Radiation Research Society.

Laboratory Website:
https://radonc.duke.edu/research-education/research-labs/radiation-and-cancer-biology/palmer-lab

Landon

Chelsea Dawn Landon

Assistant Professor of Pathology

With a research background heavily weighted in drug delivery systems in the treatment of cancer, the focus of my work has shifted to vaccination delivery methods as potential anticancer strategies. The goal of my current funding is to identify and develop a vaccine strategy delivered via the intranasal (IN) route that induces a cytotoxic T lymphocyte (CTL) response adequate for the protection/prevention of metastatic lung cancer.

I am currently working under the mentorship of Dr. Herman Staats, and in addition to the cancer immunotherapy studies, I have a strong interest in mucosal immunization and maternal immunization studies, specifically in the rabbit model.

Shiva Kumar Das

Adjunct Professor in the Department of Radiation Oncology

Intensity Modulated Radiotherapy optimization. Functional Image-guided radiotherapy (PET, SPECT). Modeling of Radiation-induced normal tissue complications (lung, cardiac) using neural nets, MART, self organizing maps, etc. Optimal selection of beam orientations for radiotherapy. Hyperthermia modeling.

Current Funded Grants:
NCI P01 CA042745-19: Hyperthermia and Perfusion Effects in Cancer Therapy Project 2: Real Time Modeling and Control Using Finite Elements and MRI (Program Director).
NCI 1R01 CA115748-01A1: Accurate Prediction of Cardiac and Lung Radiation Injury (Principal Investigator).
Varian Medical Systems: Incorporation of Functional Image-guidance in Radiotherapy Planning (Principal Investigator).

Graduate School Teaching:
MP322: Advanced Photon Beam Radiation Therapy Planning (Fall Semester)

Postdoctoral Research Associates (Past and Current):
Alan Baydush, Ph.D.
Shifeng Chen, Ph.D.
Kung-Shan Cheng, Ph.D.
Sarah McGuire, Ph.D.
Vadim Stakhursky, Ph.D.


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