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Published on: December 15, 2010
Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive
Ashwin Shinde1, Hebist Berhane1, Byung Han Rhieu1
1a Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
Abstract:
We evaluated normal tissue specific radioprotection of the oral cavity in radiosensitive Fanconi Anemia (FA) Fancd2(-/-) mice with orally established tumors using mitochondrial-targeted GS-nitroxide (JP4-039). Adult (10-12 weeks old) Fancd2(+/+), Fancd2(+/-) and Fancd2(-/-) mice (C57BL/6 background) and subgroups with orally established TC-1 epithelial cell tumors received a single fraction of 28 Gy or four daily fractions of 8 Gy to the head and neck. Subgroups received JP4-039 in F15 emulsion (F15/JP4-039; 0.4 mg/mouse), 4-amino-Tempo in F15 emulsion (F15/4-amino-Tempo; 0.2 mg/mouse) or F15 emulsion alone prior to each irradiation. Oral mucosa of Fancd2(-/-) mice showed baseline elevated RNA transcripts for Sod2, p53, p21 and Rad51 (all P < 0.0012) and suppressed levels of Nfkb and Tgfb, (all P < 0.0020) compared with Fancd2(+/+) mice. The oral mucosa in tumor-bearing mice of all genotypes showed decreased levels of p53 and elevated Tgfb and Gadd45a (P ≤ 0.0001 for all three genotypes). Intraoral F15/JP4-039, but not F15/4-amino-Tempo, modulated radiation-induced normal tissue transcript elevation, ameliorated mucosal ulceration and reduced the depletion of antioxidant stores in oral cavity tissue of all genotypes, but did not radioprotect tumors. Mitochondrial targeting makes F15/JP4-039 an effective normal tissue radioprotector for Fancd2(-/-) mice, as well as wild-type mice.
Insights
Mitochondrial-targeted GS-nitroxide (JP4-039) effectively protected normal oral tissues from radiation damage in Fanconi Anemia (FA) mice. This radioprotector did not affect tumor radiosensitivity, offering targeted normal tissue protection.
Area of Science:
- Oncology
- Radiation Oncology
- Molecular Biology
Background:
- Fanconi Anemia (FA) is a genetic disorder associated with increased radiosensitivity.
- Oral cavity tumors often require radiation therapy, which can cause significant normal tissue toxicity.
- Developing targeted radioprotectors is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To evaluate the normal tissue-specific radioprotective effects of mitochondrial-targeted GS-nitroxide (JP4-039) in the oral cavity of radiosensitive Fanconi Anemia (FA) Fancd2(-/-) mice.
- To assess the impact of JP4-039 on radiation-induced changes in gene expression and tissue damage in oral mucosa.
- To determine if JP4-039 affects tumor radiosensitivity.
Main Methods:
- Radiosensitive Fancd2(-/-) mice and wild-type littermates, with and without oral tumors, were subjected to single or fractionated head and neck irradiation.
- Mice received intraoral administration of JP4-039, 4-amino-Tempo, or vehicle control prior to irradiation.
- Gene expression analysis of oral mucosa and assessment of mucosal ulceration and antioxidant stores were performed.
Main Results:
- JP4-039 significantly modulated radiation-induced gene expression changes in oral mucosa and ameliorated mucosal ulceration across all genotypes.
- JP4-039 reduced the depletion of antioxidant stores in oral cavity tissues following irradiation.
- Importantly, JP4-039 did not provide radioprotection to the established oral tumors.
Conclusions:
- Mitochondrial-targeted JP4-039 demonstrates effective normal tissue radioprotection in the oral cavity for both FA mice and wild-type controls.
- JP4-039 offers a promising strategy for mitigating radiation-induced oral toxicity without compromising anti-tumor efficacy.
- This highlights the potential of targeted radioprotectors in improving radiation therapy for head and neck cancers.
