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
| Autor: | Li-Rong Yi, Renjun Peng, Cheng Zhang, Zongchao Zuo, Yuwen Cong, Limei Wang, Fan Bai, Zuyin Yu, Li Zhongtang, Ya-Jun Shan, Rifang Yang, Chao Yang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Radioprotective Agent Radiation-Protective Agents Pharmacology 030218 nuclear medicine & medical imaging Mice 03 medical and health sciences 0302 clinical medicine Granulocyte Colony-Stimulating Factor medicine Animals Radiology Nuclear Medicine and imaging Progenitor cell Bone Marrow Transplantation Radiation business.industry Total body irradiation Hematopoietic Stem Cells Granulocyte colony-stimulating factor Mice Inbred C57BL Transplantation Haematopoiesis medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Bone marrow Stem cell business Whole-Body Irradiation |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 103:217-228 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2018.08.002 |
| Popis: | 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-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. 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. 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. 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 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. 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. |
| Databáze: | OpenAIRE |
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