Amelioration of Head and Neck Radiation-Induced Mucositis and Distant Marrow Suppression in Fanca–/– and Fancg–/– Mice by Intraoral Administration of GS-Nitroxide (JP4-039)

Abstract

Squamous cell carcinomas of the head and neck are appearing with increased frequency in both marrow transplanted and non-transplanted Fanconi anemia (FA) patients. FA patients commonly display radiosensitivity of epithelial tissues, complicating effective radiotherapy. Fancd2 mice (C57BL/6J and 129/Sv background) demonstrate epithelial tissue sensitivity to single-fraction or fractionated irradiation to the head and neck and distant marrow suppression (abscopal effect), both ameliorated by intraoral administration of the mitochondrial-targeted antioxidant, GS-nitroxide, JP4-039. We now report that mice of two other FA genotypes, Fancg (B6) and the most prevalent human genotype Fanca (129/Sv), also demonstrate: 1. reduced longevity of hematopoiesis in long-term bone marrow cultures; 2. radiosensitivity of bone marrow stromal cell lines; and 3. head and neck radiation-induced severe mucositis and abscopal suppression of distant marrow hematopoiesis. Intraoral administration of JP4-039/F15, but not non-mitochondrial-targeted 4-amino-Tempo/F15 or F15 alone, prior to each radiation treatment ameliorated both local and abscopal radiation effects. Head and neck irradiated TGF-β-resistant SMAD3 (129/Sv) mice and double-knockout SMAD3 Fancd2 (129/Sv) mice treated daily with TGF-β receptor antagonist, LY364947, still displayed abscopal bone marrow suppression, implicating a non-TGF-β mechanism. Thus, amelioration of both local normal tissue radiosensitivity and distant marrow suppression by intraoral administration of JP4-039 in Fancg and Fanca mice supports a clinical trial of this locally administered normal tissue radioprotector and mitigator during head and neck irradiation in FA patients.

Malignant Transformation of Fanconi Anemia Complementation Group D2-deficient (Fancd2−/−) Hematopoietic Progenitor Cells by a Single HPV16 Oncogene

“…Patients with FA demonstrate evolution of acute myeloid leukemia resulting from the malignant transformation of bone marrow of hematopoietic stem cells (9). The use of the long-term bone marrow culture system mouse model of FA has a great potential value for elucidation of the sequential mutation mechanisms involved in evolution of hematopoietic malignancies (5)(6)(7). Further studies should elucidate the sequential mutational changes in Fancd2 −/− long-term bone marrow cultures and derived hematopoietic cell lines which lead to final malignant transformation by a single HPV or other viral or microbial factors including other oncogenes.…”

Amelioration of Amyotrophic Lateral Sclerosis in SOD1G93AMice by M2Microglia from Transplanted Marrow

“…SOD1 G93A and control SOD1 transgenic mice containing 4 copies of normal human SOD1 gene were obtained from the Jackson Laboratories, Bar Harbor, Maine. SOD1 G93A -green fluorescent protein (GFP + ) mice were bred according to published methods used to breed SMAD family member 3 (Smad3) −/− Fanconi anemia group D2 (Fancd2) −/− mice (59). Mice were derived from breeding pairs of SOD1 G93A and control mice.…”

“…Mice were given no irradiation, 9 Gy, or 7.0 Gy TBI using a Shephard Mark I 137 Cs γ-ray source (J. L. Shepherd, San Fernando, CA, USA), according to published methods (59). Other mice received 9 Gy cranial spinal irradiation.…”

“…Hematopoiesis in LTBMCs from SOD1 G93A mice. We tested the effect of the SOD1 G93A genotype on limiting the duration of hematopoiesis in LTBMCs as a marker of defective antioxidant capacity according to prior publications (59,(61)(62)(63)(64). Unexpectedly, SOD1 G93A mouse marrow had greater longevity than did that from SOD1 transgenic control mice.…”

Two enemies, one fight: An update of oral cancer in patients with Fanconi anemia

“…In addition, several groups are studying the use of radiation protector agents. Animal models using FANCD2 −/− (FVB/N) mice, FANCD2 −/− (C57BL/6) mice, and FANCA −/− and FANCG −/− mice showed that the intraoral administration of JP4‐039 (GS‐nitroxide) before each radiation treatment improves local normal tissue radiosensitivity and distant bone marrow suppression. These results support the need for clinical trials with this agent for future use in clinical RT for patients with FA.…”