17α-Ethinyl-androst-5-ene-3β, 17β-diol, a novel potent oral radioprotective agent, confers radioprotection of hematopoietic stem and progenitor cells in a granulocyte colony stimulating factor-independent manner.

PURPOSE: The risk of radiation exposure is considered to have increased in recent years. For convenience and simple administration, development of an effective orally administered radioprotective agent is highly desirable. The steroid 5-AED has been evaluated as both a radioprotector and a radiomitigator in mice and nonhuman primates, however, poor oral bioavailability has limited its development, while a variant compound, 17α-Ethinyl-androst-5-ene-3β, 17β-diol (EAD), exhibits significant oral bioavailability. We investigated the radioprotective effects of EAD via oral administration in mice.

METHODS AND MATERIALS: Survival assays were performed in lethally (9.0-10.0 Gy) irradiated mice. peripheral blood cell counts were monitored in lethally (9.5 Gy) or sublethally (6.5 Gy) irradiated mice. Histological analysis of bone marrow (BM), and frequency and functional analysis of hematopoietic stem and progenitor cells (HSPCs) in 6.5 Gy irradiated mice were performed. To investigate multilineage engraftment of irradiated HSCs after BM transplantation, competitive repopulation assays were conducted. Plasma granulocyte-colony stimulating factor (G-CSF) was measured by ELISA.

RESULTS: Oral administration of EAD on 3 consecutive days before irradiation conferred 100% survival in mice, against otherwise 100% death, at a 9.5 Gy lethal dose of total body radiation. EAD ameliorated radiation-induced pancytopenia at the same dose. EAD augmented BM cellular recovery and colony-forming ability, promoted HSPC recovery, and expanded the pool of functionally superior hematopoietic stem cells in the BM of sublethally irradiated mice. Unlike 5-AED, EAD did not increase G-CSF levels in mice and exhibited no therapeutic effects on hematological recovery post-irradiation; nevertheless, its radioprotective efficacy was superior to that of 5-AED.

CONCLUSIONS: Our findings demonstrate the radioprotective efficacy of EAD and reveal that the 17α-Ethinyl group is essential for its oral activity. Given its oral efficacy and low toxicity, EAD has potential as an optimal radioprotector for use by first responders as well as at-risk civilian populations.