HE2100 and HE3204 protect Rhesus Macaques from chemotherapy or radiation induced myelosuppression

Abstract

6668 Background: HE2100, androst-5-ene-3β,17β-diol, and HE3204 are naturally occurring and synthetic adrenal steroid hormones, respectively. Prophylactic and therapeutic HE2100 studies of lethally irradiated rodents demonstrated a significant survival advantage for treated groups (Whitnall et. al., Int. J. Immunopharm.2000). Rodent studies with either HE2100 or HE3204 demonstrated protection against chemotherapy-induced myelosuppression. Methods: The current study investigated the effects of these compounds in (1) a non-human primate model with induced myelosuppression from chemotherapy or ionizing radiation and (2) on primitive (Long-Term Culture-Initiating Cells-LTC-IC), lineage committed (Granulocyte-Macrophage Colony-Forming Cells-GM-CFC) and bone marrow mesenchymal progenitor cells. Non-human primates were given carboplatin, 35 mg/kg, 36 hrs. prior to 5 daily sc injections of HE2100 or HE3204 or 2–4 hours after sublethal total body irradiation. Blood counts were measured daily during severely neutropenic days. Results: HE2100 showed a decrease in the number of days of severe neutropenia (<500cells/uL) in the sub-lethally irradiated macaques from 7 days (vehicle) to 2 days at the highest dose (p=0.019) and reduced the days of severe neutropenia induced by carboplatin from 5.3 (vehicle) to 0.7. HE2100 increased: (1) GM-CFC-derived colony numbers by 36% using standard in vitro assays (p= <0.001); (2) at wk 4 of LTBMC the GM-CFC number by 280% (p=0.035): and (3) bone marrow mesenchymal progenitor cells in vitro. HE3204 completely eliminated severe neutropenia from chemotherapy, 5.3 days for vehicle control to 0 (p=0.03). Conclusions: This class of compounds expands committed and primitive bone marrow progenitor cells and affords significant protection from chemo or radiation induced myelosuppression in non-human primates. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hollis Eden Pharmaceuticals, Inc. Hollis Eden Pharmaceuticals, Inc. Hollis Eden Pharmaceuticals, Inc.