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12635 E. Montview Blvd., Suite 270
Aurora, CO 80045
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Amelioration of Ionizing Irradiation Damage to the Oral Cavity/Oropharynx of Radiosensitive Fanconi Anemia FancD2-/- Mice by GS-Nitroxide JP4-039
Investigator: Ashwin Shinde
Mentors: Joel Greenberger, MD and Michael Epperly, PhD
Background: The DNA repair defect in Fanconi Anemia (FA) patients makes radiotherapy of head and neck cancers a challenge. Unacceptable toxicity in these patients, principally mucositis, is a dose limiting problem. We tested intraoral delivery of the mitochondrial-targeted antioxidant, JP4-039, in a novel F15 emulsion, to reduce mucositis in fractionated irradiated FA mice with orthotopic tumors.
Methods: Adult 10-12 week old Fancd2+/+, Fancd2+/-, and Fancd2-/- mice from C57BL/6 background were injected in the left cheek pouch with 1 x 107 TC-1 squamous cell carcinoma cells. Tumors were allowed to grow until palpable and measureable by calipers. Mice were then irradiated to either 28 Gy or 8 Gy x 4 daily fractions to the oral cavity. Subgroups of mice (N=4/group) received intraoral JP4-039/F15 (100 ul containing 4 mg/ml of drug) 10 minutes prior to irradiation, F15 alone or irradiation alone. Tumor size was measured daily. Five days after the last radiation dose, mice were sacrificed, and tumors and tongue tissue were removed for histopathology. Statistical analysis was performed using Student’s t-test, with a p-value < 0.05 considered significant.
Results: Intraoral JP4-039/F15 prior to either 28 Gy or 8 Gy x 4 resulted in significantly decreased oral cavity ulceration (p < 0.001). Following 8 Gy x 4, F15-JP4-039 treated Fancd2-/- knockout mice had 47.8 + 11.1% of the tongue ulcerated compared to 81.7 ± 11.6% ulceration in untreated mice (p < 0.001). Results in F15-JP4-039 treated irradiated heterozygotes and wild-type Fancd2+/+ mice (34.1 ± 21.2 or 16.9 ± 12.6% ulceration, respectively) were also improved compared to untreated irradiated mice (88.3 ± 8.0 or 76.3 ± 17.2% ulceration, respectively) (p < 0.001 for all groups). In contrast,F15 alone did not reduce ulceration.Fancd2-/- F15-JP4-039 treated mice still displayed increased ulceration compared to Fancd2+/+ mice (47.8 + 11.1% and 16.9 ± 12.6%, respectively, p < 0.0001), Both single fraction and fractionated irradiation controlled tumors at 5 days in Fancd2+/+,Fancd2+/-, and Fancd2-/- mice (0.4 ± 0.3, 0.05 ± 0.05, or 0.1 ± 0.1 mm3, respectively) compared to unirradiated controls (2.1 ± 0.4, 1.9 ± 0.5, or 3.1 ± 0.1 mm3, respectively, p ≤ 0.027). Tumor size was comparably reduced in all irradiated groups, including those that received JP4-039/F15 or F15 alone.
Conclusions: Intraoral JP4-039 protects normal tissue in irradiated FA mice without associated tumor protection.
Supported by NIAID/NIH U19-A1068021, the Fanconi Anemia Research Foundation, and the AΩA Carolyn L. Kuckein Student Research Fellowship.
Last updated: 10/2/2014
Updated on September 3, 2014.