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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.
Int J Radiat Oncol Biol Phys. 2019 01 01; 103(1):217-228.IJ

Abstract

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.

Authors+Show Affiliations

Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.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.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.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.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China.Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology, Beijing, China. Electronic address: congyw@nic.bmi.ac.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30103023

Citation

Bai, Fan, et al. "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." International Journal of Radiation Oncology, Biology, Physics, vol. 103, no. 1, 2019, pp. 217-228.
Bai F, Wang L, Li Z, et al. 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. Int J Radiat Oncol Biol Phys. 2019;103(1):217-228.
Bai, F., Wang, L., Li, Z., Yi, L., Zuo, Z., Zhang, C., Shan, Y., Yang, C., Peng, R., Yang, R., Yu, Z., & Cong, Y. (2019). 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. International Journal of Radiation Oncology, Biology, Physics, 103(1), 217-228. https://doi.org/10.1016/j.ijrobp.2018.08.002
Bai F, et al. 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. Int J Radiat Oncol Biol Phys. 2019 01 1;103(1):217-228. PubMed PMID: 30103023.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Bai,Fan, AU - Wang,Limei, AU - Li,Zhongtang, AU - Yi,Lirong, AU - Zuo,Zongchao, AU - Zhang,Cheng, AU - Shan,Yajun, AU - Yang,Chao, AU - Peng,Renjun, AU - Yang,Rifang, AU - Yu,Zuyin, AU - Cong,Yuwen, Y1 - 2018/08/10/ PY - 2018/03/06/received PY - 2018/06/18/revised PY - 2018/08/01/accepted PY - 2018/8/14/pubmed PY - 2019/7/10/medline PY - 2018/8/14/entrez SP - 217 EP - 228 JF - International journal of radiation oncology, biology, physics JO - Int. J. Radiat. Oncol. Biol. Phys. VL - 103 IS - 1 N2 - 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. SN - 1879-355X UR - https://www.unboundmedicine.com/medline/citation/30103023/17α_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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0360-3016(18)33530-2 DB - PRIME DP - Unbound Medicine ER -