Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin

Abstract

Normal tissue damage after head and neck radiotherapy involves a continuum of pathologic events to the mucosa, tongue and salivary glands. We examined the radioprotective effects of MnBuOE, a redox-active manganese porphyrin, at three stages of normal tissue damage: immediate (leukocyte endothelial cell [L/E] interactions), early (mucositis) and late (xerostomia and fibrosis) after treatment. In this study, mice received 0 or 9 Gy irradiation to the oral cavity and salivary glands ± MnBuOE treatment. Changes in leukocyte-endothelial cell interactions were measured 24 h postirradiation. At 11 days postirradiation, mucositis was assessed with a cathepsin-sensitive near-infrared optical probe. Stimulated saliva production was quantified at 11 weeks postirradiation. Finally, histological analyses were conducted to assess the extent of long-term effects in salivary glands at 12 weeks postirradiation. MnBuOE reduced oral mucositis, xerostomia and salivary gland fibrosis after irradiation. Additionally, although we have previously shown that MnBuOE does not interfere with tumor control at high doses when administered with radiation alone, most head and neck cancer patients will be treated with the combinations of radiotherapy and cisplatin. Therefore, we also evaluated whether MnBuOE would protect tumors against radiation and cisplatin using tumor growth delay as an endpoint. Using a range of radiation doses, we saw no evidence that MnBuOE protected tumors from radiation and cisplatin. We conclude that MnBuOE radioprotects normal tissue at both early and late time points, without compromising anti-tumor effects of radiation and cisplatin.

CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+

“…Consistent with the histopathology findings, we observed gross tissue deformation in the small number of mice that died mid-way through the administration period. A recent study showed the radioprotective effects of MnBuOE on salivary glands and mouth mucosa at a maintenance dose as low as 0.1 mg/kg [43] and suggested that MnHex might have been radioprotective of hippocampal neurogenesis at much lower doses than the one we used in this study.…”

H2O2‐Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways

“…The impact of MnTnBuOE-2-PyP 5+ combined with radiation was demonstrated in the suppression of the FaDu human epithelial cell line from squamous cell carcinoma of the hypopharynx in a mouse sc flank xenograft model. The tumor radiosensitizing effect of MnP was discussed with regard to the significant influx of tumoricidal M1 tumorassociated macrophages [54,95]. Further, MnTnBuOE-2-PyP 5+ reduced radiation-mediated mucositis, xerostomia, and fibrosis of salivary glands.…”

ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer

“…Another report from this team discovered that lower doses of MnBuOE mitigated cisplatin-induced oral ulcer formation, bleeding, and furfuration in the radiation area. MnBuOE did not meddle with RT/cisplatin-regulated neoplasm growth [110]. BMX-001 is undergoing phase I clinical trials concerning its safety and pharmacokinetic and radiation protection in conditions of locally advanced head and neck cancer (clinical trial number: NCT02990468).…”