Effects of a Novel Orally Bioavailable Small Molecule (Imidazolyl Ethanamide Pentandioic Acid) on Acute Radiation Syndrome

Introduction

Acute radiation syndrome (ARS) develops within 24 hours of exposure to ionizing radiation. Leukocyte growth factors have been used to reduce mortality and mitigate the hematopoietic symptoms of ARS. Three subcutaneously applied radiomitigators G-CSF, Peg-G-CSF and GM-CSF have been approved by the FDA as medical countermeasures but few others are under development. Imidazolyl ethanamide pentandioic acid (IEPA, Myelo001) is a novel small molecule for the treatment of ARS. Preclinical and clinical studies have shown that IEPA applied orally or intraperitoneally was effective in reducing hematopoietic symptoms caused by radiation and chemotherapy.

Objective

To investigate the effects of IEPA as a radioprotector (prophylactic) and radiomitigator (therapeutic) for ARS and hematopoietic syndrome of ARS (H-ARS).

Methods

Multiple oral or intraperitoneal administrations of IEPA (25 or 50 mg/kg doses) and radiation levels of 5.8 Gy (estimated LD25/30) and 6.0 Gy (estimated LD50/30) on mortality, body weight and bone marrow cellularity were assessed in a mouse model. 205 C57BL/6 mice were subdivided into 1 unirradiated group, 6 groups exposed to 5.8 Gy, and 2 groups exposed to 6.0 Gy. Prophylactic treatment (25 or 50 mg/kg) was started 3 days before total-body irradiation, while therapeutic treatment (50 mg/kg) was begun 24 h post exposure. The 6 LD25/30 groups consisted of a vehicle control group (VL; 2), twice daily intraperitoneally administered IEPA (ML; 3), orally twice a day (ML; 4) or once a day (ML; 5), G-CSF positive control subcutaneously administered once a day (GL; 6) or in combination with IEPA (M/GL; 7). The 2 LD50/30 groups consisted of a vehicle control group (VH; 8) and a group administered IEPA orally once a day (MH; 9). The experiments assessed mortality using Kaplan-Meier estimator, body weight and bone marrow cellularity over the course of 30 days with prescheduled sacrifices of subgroups on days 7, 14 and 30.

Results

No significant benefit of prophylactic and therapeutic treatment on survival in the lower (5.8 Gy) irradiation group was detected. Groups ML; 3 and ML; 4 had a dose reduction factor (DFR) < 1 vs VL; 2 whereas ML; 5, GL; 6 and M/GL; 7 had a DRFs > 1. In the high radiation group (6.0 Gy), the Kaplan-Meier estimator revealed an increase in survival (85 %) after therapy compared to controls (56 %). The dose reduction factor in group MH; 9 compared to the controls (VH; 8) was 1.5. The highest protective effect on body weight was observed in the therapeutic regimen (MH; 9) used for 6.0 Gy exposure, which showed a positive effect on days 15, 21 and 30. Therapeutic IEPA treatment mitigated the impact of radiation on bone marrow cellularity. A pronounced effect on peripheral hematology was neither observed in the prophylactic, therapeutic IEPA nor the positive control G-CSF treated groups.

Conclusions

Different routes of administration and doses of IEPA in the prophylactic groups did not alter ARS symptoms. However, therapeutic treatment in the LD25/30 setting with IEPA and G-CSF, and the LD50/30 setting with IEPA at a dose of 50 mg/kg showed a reduction in mortality and weight loss compared to the controls. Additionally, IEPA treatment mitigated the impact of radiation on bone marrow cellularity. Analysis of peripheral blood did not reveal significant differences across the treatment groups probably due to no optimal time point analysis. Limitations included the small size of the prophylactically treated groups exposed to a low radiation dose.

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