Amelioration of Mucositis in Proton Therapy of Fanconi Anemia Fanca^−/− Mice by JP4-039

Abstract

Background/Aim: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice. Materials and Methods: Fanca-/and Fanca +/+ bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and β-Galactosidase senescence analysis. Fanca-/and Fanca +/+ mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis. Results: JP4-039 reduced oral cavity ulceration in Fanca-/mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression. Conclusion: JP4-039 protected Fanca-/and Fanca +/+ cells and mouse oral cavity from both proton and photon radiation.

Chemical Carcinogen (Dimethyl-benzanthracene) Induced Transplantable Cancer in Fanconi Anemia (Fanca−/−) Mice

“…Radiation protective drugs have been developed to increase the therapeutic ratio of irradiation in animal models using transplantation of orthotopic tumors. Orthotopic tumors have been derived from wild type mice that do not have the FA genotype (25)(26)(27)(28)(29). Furthermore, the radiobiology of a mouse FA cancer cell line has not been well characterized.…”

“…Recent research has focused on methods to reduce the toxicity of chemoradiotherapy in patients with FA (20)(21)(22)(23)(24)(25)(26)(27). The development of new agents to protect normal tissues, while compromising the viability of residual tumor cells has already led to the discovery of novel radioprotective agents including the mitochondrial targeted nitroxide JP4-039 (23)(24)(25)(26)(27)(28)(29).…”

Models for Translational Proton Radiobiology—From Bench to Bedside and Back

“…Their advantages over large animal models are the small size, which facilities housing, lower economical expenses, as well as short reproductive cycles and lifespans. Additionally, genetically engineered mice can be utilized to investigate the relevance of specific genes, and their responses and changes to radiation [192,193]. In radiobiology, murine models are typically used to study the elaborated mechanisms of radiation-induced normal tissue and tumor response.…”

Oral and Dental Manifestations of Fanconi Anemia

“…FA patients with advanced oral cancer require a combination of surgery, radiotherapy, and chemotherapy for appropriate treatment. To reduce the adverse effects of radiation in FA patients with oral cancer or head and neck cancer, experimental tests are performed on FA mice irradiated with proton therapy to reduce the occurrence of inflammation of the oral mucosa [28]. Infection control is the most important part of dental treatment for FA patients.…”