Novel Hormone HE2100 Protects Rhesus Macaques From Lethal Total Body Irradiation (TBI)- Induced Severe Neutropenia and Thrombocytopenia

Abstract

Purpose/Objective: HE2100 is a naturally occurring adrenal steroid hormone. Studies of lethally irradiated rodents demonstrated a significant survival advantage for HE2100 treated groups (Whitnall et. al., Int. J. Immunopharm.2000). Previously, (ASTRO-2004) we reported a reduction in lethality in Rhesus macaques following 6.00 Gy of TBI. The objectives of the current studies were to further investigate the effects of this compound to prevent severe radiation induced neutropenia and thrombocytopenia and to enhance survival following lethal irradiation in a non-human primate (NHP) model. We report a meta-analysis of 6 studies involving 108 Rhesus macaques. Materials/Methods: Studies investigated effects of HE2100 in non-human primates (NHP) with induced myelosuppression/thrombocytopenia from ionizing radiation. NHP studies were performed in 6 separate studies of 108 NHP (untreated/vehicle and 5-36.5 mg/kg HE2100 IM daily once or x5) administered 2–3 hours after 6.00 Gy to 6.34 Gy, cobalt-60 or 6 MV X-ray TBI. No clinically supportive measures i.e. transfusions or antibiotics were given during the study. NHP were continuously monitored for temperature. Blood counts were measured daily during expected neutropenic days. Strict euthanasia criteria were observed to allay animal suffering. Studies were performed under Institutional Animal Control and Use Committee review and approval. Results: In the HE2100 treated groups 13/54 animals died (LD24) compared to 24/54 (LD44) in the untreated or vehicle control groups (p=0.0419). The cumulative incidence of days of severe neutropenia (absolute neutrophil count < 500 cells/microL) was reduced by 13.5 percentage points (p=0.0162), whereas the cumulative incidence of days of thrombocytopenia (platelet count < 20,000 platelets/microL) was reduced by 9.2 percentage points (p<0.001). Death in all NHP correlated to opportunistic infections from gut and skin flora with death resulting from hemorrhagic sepsis and/or sepsis. Following radiation-induced injury, HE2100-related changes (increased cellularity) occurred in the bone marrow, spleen, and lymph nodes Conclusions: HE2100 significantly reduced mortality in lethally irradiated Rhesus macaques. Findings compatible with hematopoetic stimulation were observed in Rhesus monkeys administered HE2100 daily for five days. HE2100 stimulates a multi-lineage recovery of the bone marrow following total body ionizing radiation injury in NHP.