Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.
Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Int J Radiat Oncol Biol Phys. 2019 Jan 1;103(1):217-228. doi: 10.1016/j.ijrobp.2018.08.002. Epub 2018 Aug 10.
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-androstene-3β, 17β-diol (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. 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.
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. We performed histologic analysis of bone marrow (BM) and frequency and functional analysis of hematopoietic stem and progenitor cells in mice irradiated with 6.5 Gy. To investigate multilineage engraftment of irradiated hematopoietic stem cells after BM transplantation, competitive repopulation assays were conducted. Plasma granulocyte colony-stimulating factor was measured by enzyme-linked immunosorbent assay.
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 irradiation. EAD ameliorated radiation-induced pancytopenia at the same dose. EAD augmented BM cellular recovery and colony-forming ability, promoted hematopoietic stem and progenitor cell 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 granulocyte colony-stimulating factor levels in mice and exhibited no therapeutic effects on hematologic recovery after irradiation; nevertheless, its radioprotective efficacy was superior to that of 5-AED.
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.
近年来，人们认为辐射暴露的风险有所增加。为了方便和简单管理，开发一种有效的口服放射性保护剂是非常理想的。甾体 5-雄烯-3β，17β-二醇（5-AED）已在小鼠和非人灵长类动物中被评估为放射保护剂和放射减毒剂；然而，较差的口服生物利用度限制了其发展。一种变体化合物-17α-乙炔基-雄甾-5-烯-3β，17β-二醇（EAD）表现出显著的口服生物利用度。我们通过口服给药在小鼠中研究了 EAD 的放射保护作用。
在致死剂量（9.0-10.0Gy）照射的小鼠中进行生存分析。在致死剂量（9.5Gy）或亚致死剂量（6.5Gy）照射的小鼠中监测外周血细胞计数。我们对 6.5Gy 照射的小鼠的骨髓（BM）进行组织学分析，并对造血干细胞和祖细胞的频率和功能进行分析。为了研究 BM 移植后照射造血干细胞的多谱系植入，进行了竞争性再群体测定。通过酶联免疫吸附试验测量血浆粒细胞集落刺激因子。
在照射前连续 3 天口服 EAD，可使 9.5Gy 全身照射的致死剂量的小鼠 100%存活，否则 100%死亡。EAD 可改善相同剂量照射引起的全血细胞减少症。EAD 增强了 BM 细胞的恢复和集落形成能力，促进了造血干细胞和祖细胞的恢复，并扩大了亚致死剂量照射小鼠 BM 中功能优越的造血干细胞池。与 5-AED 不同，EAD 不会增加小鼠中的粒细胞集落刺激因子水平，并且对照射后血液学恢复没有治疗作用；然而，它的放射保护效果优于 5-AED。
我们的研究结果证明了 EAD 的放射保护效果，并表明 17α-乙炔基是其口服活性所必需的。鉴于其口服疗效和低毒性，EAD 有可能成为一线人员和高危平民群体的理想放射保护剂。
