Naslov
Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model
(A novel manganese-porphyrin superoxide dismutase-mimetic widens the therapeutic margin in a pre-clinical head and neck cancer model)

Autori
Ashcraft, Kathleen A. ; Boss, Mary-Keara ; Tovmasyan, Artak ; Choudhury, Kingshuk Roy ; 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. ; Spasojević, Ivan ; Batinić-Haberle, Ines ; Dewhirst, Mark W.

Izvornik
International journal of radiation oncology, biology, physics (0360-3016) 93 (2015), 4; 892-900

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Mn porphyrin ; oxidative stress modifier ; radioprotectivity ; radiosensitizing

Sažetak
Purpose Normal tissue injury is dose limiting for radiotherapy (RT) in nearly every application. This provides strong rationale for developing new classes of novel radioprotectors. The caveat is that radioprotective drugs must be selective for normal tissue and not tumor. Here we tested the effects of a novel Mn porphyrin oxidative stress modifier, MnBuOE for its radioprotective and radiosensitizing properties in normal tissue vs. tumor, respectively. Methods Murine oral mucosa and salivary glands were treated with a range of radiation doses, ±MnBuOE to establish the dose effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital NIR imaging of cathepsin activity, assessment of salivation and histological 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 RT doses were administered to establish the radiation dose effect curve. The TCD50 values ±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 to controls. The dose modifying factor, based on the ratio of TCD50 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.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA