Novel synthetic compounds, known as manganese porphyrins (MnPs), have been designed to shift the redox status of both normal cells and cancer cells. When MnPs are coupled with cancer therapies, such as radiation, they have been shown to sensitize tumor cells to treatment and protect normal tissues from damage through the modulation of the redox status of various tissue types. Until now, our preclinical studies have focused on local effects of MnPs and radiation; however, we recognize that successful outcomes for cancer patients involve control of tumor cells throughout the body. In this study, using murine orthotopic mammary tumor models, we investigated how MnPs and radiation influence the development of distant metastasis. We hypothesized that the combination of MnP (MnP/RT), such as MnTnBuOE-2-PyP5+ and radiation treatment (RT) would increase local tumor control via a shift in the intratumoral redox environment, leading to subsequent downregulation of HIF-1 in the primary tumor. Secondarily, we hypothesized that these primary tumor treatment effects would result in a reduction in pulmonary metastatic burden. Balb/c mice with orthotopic 4T1 mammary carcinomas were treated with saline, MnP, RT or MnP/RT. We found MnP/RT did extend local tumor growth delay and overall survival compared to controls and was associated with increased intratumoral oxidative stress. However, the primary tumor growth delay observed with MnP/RT was not associated with a reduced pulmonary metastatic burden. Future directions to investigate the effects of MnP/RT on the development of distant metastasis may include modifications to the radiation dose, the experimental timeline or using a murine mammary carcinoma cell line with a less aggressive metastatic behavior. Clinical trials are underway to investigate the clinical utility of MnTnBuOE-2-PyP5+ for patients undergoing radiotherapy for various tumor types. The promising preclinical data from this study, as well as others, provides support that MnP/RT has the potential to improve local tumor control for these patients.
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February 2021
Research Article|
December 02 2020
Manganese Porphyrin and Radiotherapy Improves Local Tumor Response and Overall Survival in Orthotopic Murine Mammary Carcinoma Models
Mary-Keara Boss
;
Mary-Keara Boss
1
a Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523
1 Address for correspondence: Colorado State University, Department of Environmental and Radiological Health Sciences, 300 W. Drake Rd. Fort Collins, CO 80523; email: keara.boss@colostate.edu.
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Rebecca E. Oberley-Deegan
;
Rebecca E. Oberley-Deegan
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Ines Batinic-Haberle
;
Ines Batinic-Haberle
d Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710
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Geoffrey A. Talmon
;
Geoffrey A. Talmon
c Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Jason A. Somarelli
;
Jason A. Somarelli
e Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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Shengnan Xu
;
Shengnan Xu
e Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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Elizabeth A. Kosmacek
;
Elizabeth A. Kosmacek
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Brandon Griess
;
Brandon Griess
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Shakeel Mir
;
Shakeel Mir
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Shashank Shrishrimal
;
Shashank Shrishrimal
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Melissa Teoh-Fitzgerald
;
Melissa Teoh-Fitzgerald
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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Ivan Spasojevic
;
Ivan Spasojevic
e Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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Mark W. Dewhirst
Mark W. Dewhirst
d Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710
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Radiat Res (2021) 195 (2): 128–139.
Article history
Received:
April 17 2020
Accepted:
October 06 2020
Citation
Mary-Keara Boss, Rebecca E. Oberley-Deegan, Ines Batinic-Haberle, Geoffrey A. Talmon, Jason A. Somarelli, Shengnan Xu, Elizabeth A. Kosmacek, Brandon Griess, Shakeel Mir, Shashank Shrishrimal, Melissa Teoh-Fitzgerald, Ivan Spasojevic, Mark W. Dewhirst; Manganese Porphyrin and Radiotherapy Improves Local Tumor Response and Overall Survival in Orthotopic Murine Mammary Carcinoma Models. Radiat Res 1 February 2021; 195 (2): 128–139. doi: https://doi.org/10.1667/RADE-20-00109.1
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