[show abstract][hide abstract] ABSTRACT: Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development.
[show abstract][hide abstract] ABSTRACT: Total-body irradiation (TBI) doses in the range of 2-8 Gy are associated with a drop in peripheral blood counts, decreased bone marrow cellularity, and hematopoietic syndrome. Radiation mitigators must be safe for individuals likely to recover spontaneously.
Female C57BL/6HNsd mice exposed to 9.0 and 9.15 Gy TBI, received intraperitoneal (10 mg/kg) JP4-039, a novel radiation mitigator, 24 hours after irradiation and were followed for hematopoietic recovery.
Irradiated mice showed reduced peripheral blood lymphocytes and neutrophils and bone marrow cellularity at day 5. Serum electrolytes, liver and renal function tests showed no deleterious effect of JP4-039-after irradiation, and no reduction in survival compared to irradiated controls. Marrow recovery measured as cellularity, and hematopoietic colony-forming cells including primitive granulocyte-erythroid-megakaryocyte-monocytes (GEMM), reached pre-irradiation levels by day 30 in JP4-039 treated groups. Mice receiving single or multiple administrations of JP4-039 showed an early return of CFU-GEMM.
JP4-039 (GS-Nitroxide) is a safe radiation mitigator in mice warranting studies in larger animals and potentially a Phase I Clinical Trial.
In vivo (Athens, Greece) 25(3):315-23. · 1.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: this study evaluated esophageal radioprotection by the Gramicidin S (GS) derived-nitroxide, JP4-039, a mitochondrial targeting peptide-isostere covalently-linked to 4-amino-Tempo, delivered in a novel swallowed oil-based (F15) formulation.
C57BL/6HNsd female mice received intraesophageal F15 formulation containing JP4-039 (4 mg/ml in 100 microl volumes) 10 minutes before 28 or 29 Gy upper body irradiation compared to MnSOD-PL (100 microl containing 100 microg plasmid) 24 hours prior to irradiation. Subgroups received 1 × 10(7) C57BL/6HNsd, GFP(+) male bone marrow cells intravenously 5 days after irradiation.
JP4-039/F15 or MnSOD-PL increased survival compared to irradiated controls (p<0.0001 for either). Marrow injection further increased survival (p=0.0462 and 0.0351, respectively). Esophagi removed at 1, 3, 7, 14, 24, or 60 days showed bone marrow-derived cells in the esophagi.
intraesophageal GS-nitroxide radioprotection is mediated primarily through recovery of endogenous esophageal progenitor cells.
In vivo (Athens, Greece) 24(6):811-9. · 1.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Esophagitis is a significant toxicity of radiation therapy for lung cancer. In this study, reduction of irradiation esophagitis in mice, by orally administered p53/Mdm2/Mdm4 inhibitor, BEB55, or the GS-nitroxide, JP4-039, was evaluated.
BEB55 or JP4-039 in F15 (liposomal) formulation was administered intraesophageally to C57BL/6 mice prior to thoracic irradiation of 29 Gy × 1 or 11.5 Gy × 4 thoracic irradiation. Progenitor cells were sorted from excised esophagus, and nitroxide was quantified, by electron paramagnetic resonance (EPR). Mice with Lewis lung carcinoma (3LL) orthotopic lung tumors were treated with BEB55 or JP4-039 prior to 20 Gy to determine if the drugs would protect the tumor cells from radiation.
Intraesophageal BEB55 and JP4-039 compared to formulation alone increased survival after single fraction (p=0.0209 and 0.0384, respectively) and four fraction thoracic irradiation (p=0.0241 and 0.0388, respectively). JP4-039 was detected in esophagus, liver, bone marrow, and orthotopic Lewis lung carcinoma (3LL) tumor. There was no significant radiation protection of lung tumors by BEB55 or JP4-039 compared to formulation only as assessed by survival (p=0.3021 and 0.3693, respectively). Thus, BEB55 and JP4-039 safely ameliorate radiation esophagitis in mice.
In vivo (Athens, Greece) 25(6):841-8. · 1.22 Impact Factor