Abstract 492: Esophageal administration of manganese superoxide dismutase plasmid liposomes (MnSOD-PL) reverses thoracic irradiation sensitivity of nitric oxide synthase one homologous recombinant negative (NOS1 -/-) mouse

Abstract

Abstract NOS1 -/- mice are more sensitive to 29 Gy thoracic or 9.5 Gy total body irradiation (TBI) than control C57BL/6NHsd, or NOS2 -/- or NOS3 -/- mice (p < 0.0001 and p = 0.0006). Histological examination of the esophagus, lungs, heart and intestine revealed no explanation of the rapid death of NOS1 -/- mice. Blood and bone marrow isolates six days after TBI (1 day before the NOS1 -/- mouse death) showed similar decrease in blood counts for all the mouse strains. NOS1 -/- mouse marrow irradiated to doses ranging from 0 to 8 Gy showed CFU-GM, BFU-E and CFU-GEMM radiosensitivity similar to that from control mice. There were also no differences in serum electrolytes, liver or renal function tests in irradiated NOS1 -/- compared to C57BL/6NHsd mice. RNA extracted from esophagus, stomach or intestine at day 0, 1 or 6 following 9.5 total body irradiation showed by qualitative RT-PCR analysis of TNF-σ, NF-κβ, and INF-γ similar cytokine expression between NOS1 -/- and C57BL/6NHsd mice. NOS1 -/- and C57BL/6NHsd mice were irradiated to 9.5 Gy total body or 20 Gy to the thoracic cavity and observed by video camera. NOS1 -/- mice had seizures before death following both TBI or thoracic irradiation, while no seizures were detected in dying C57BL/6NHsd mice. NOS1 -/- mice irradiated to 9.5 Gy to the brain (with the remainder of the body shielded) did not produce death from seizures. NOS1 -/- were intraesophageally administered MnSOD-PL (100 µg plasmid DNA) and irradiated to 20 Gy to the upper body 24 hr later. NOS1 -/- mice administered MnSOD-PL had normalized survival compared to control irradiated NOS1 -/- mice: 50% survival at 12 days for irradiated control NOS1 -/- mice compared to 128 days for MnSOD-PL treated NOS1 -/- mice (p = 0.0311). The data indicate that esophageal neuronal abnormalities which cause pyloric stenosis in the strain may be responsible for both the rapid thoracic irradiation sensitivity leading to seizure and its reversal by intraesophageal MnSOD-PL gene therapy. Supported by NIAID grant U19AI068021, and NIH grant T32AG21885 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 492.