BIO 300: a promising radiation countermeasure under advanced development for acute radiation syndrome and the delayed effects of acute radiation exposure

References

• Koenig KL, Goans RE, Hatchett RJ, et al. Medical treatment of radiological casualties: current concepts. Ann Emerg Med. 2005;45:643–652.
   PubMed Web of Science ®Google Scholar
• Ohnishi T. The disaster at Japan’s Fukushima-Daiichi nuclear power plant after the March 11, 2011 earthquake and tsunami, and the resulting spread of radioisotope contamination. Radiat Res. 2012;177:1–14.
   PubMed Web of Science ®Google Scholar
• Williams JP, McBride WH. After the bomb drops: a new look at radiation-induced multiple organ dysfunction syndrome (MODS). Int J Radiat Biol. 2011;87:851–868.
   PubMed Web of Science ®Google Scholar
• Need JT, Mothershead JL. Strategic national stockpile program: implications for military medicine. Mil Med. 2006;171:698–702.
   PubMed Web of Science ®Google Scholar
• Fushiki S. Radiation hazards in children - lessons from Chernobyl, Three Mile Island and Fukushima. Brain Dev. 2013;35:220–227.
   PubMed Web of Science ®Google Scholar
• Hu TW, Slaysman KS. Health-related economic costs of the Three-Mile Island accident. Socioecon Plann Sci. 1984;18: 183–193.
   PubMed Web of Science ®Google Scholar
• Andersson KG, Mikkelsen T, Astrup P, et al. Estimation of health hazards resulting from a radiological terrorist attack in a city. Radiat Prot Dosimetry. 2008;131:297–307.
   PubMed Web of Science ®Google Scholar
• Bar-Dayan Y, Hagby M, Goldberg A, et al. Health implications of radiological terrorism: perspectives from Israel. J Emerg Trauma Shcock. 2009;2(2):117–123.
   PubMedGoogle Scholar
• Biological Effects of Ionizing Radiation VII. Health risks from exposure to low levels of ionizing radiation. Washington, DC: National Academy Press; 2005
   Google Scholar
• Gale RP, Armitage JO. Are we prepared for nuclear terrorism? N Engl J Med. 2018;378:1246–1254.
   PubMed Web of Science ®Google Scholar
• Seed TM. Radiation protectants: current status and future prospects. Health Phys. 2005;89:531–545.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. Int J Radiat Biol. 2017;93:851–869.
   PubMed Web of Science ®Google Scholar
• Singh VK, Hanlon BK, Santiago PT, et al. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use. Int J Radiat Biol. 2017;93:885–906.
   PubMed Web of Science ®Google Scholar
• Singh VK, Garcia M, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int J Radiat Biol. 2017;93(9):870–884.
   PubMed Web of Science ®Google Scholar
• Stone HB, Moulder JE, Coleman CN, et al. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3–4, 2003. Radiat Res. 2004;162:711–728.
   PubMed Web of Science ®Google Scholar
• McCann DGC. Radiation poisoning: current concepts in the acute radiation syndrome. Am J Clin Med. 2006;3:13–21.
   Google Scholar
• Armed Forces Radiobiology Research Institute. Medical management of radiological casualities. 4th ed. Bethesda, MD, USA: Armed Forces Radiobiology Research Institute; 2013.
   Google Scholar
• Singh VK, Newman VL, Romaine PL, et al. Radiation countermeasure agents: an update (2011–2014). Expert Opin Ther Pat. 2014;24:1229–1255.
   PubMed Web of Science ®Google Scholar
• Manas ES, Xu ZB, Unwalla RJ, et al. Understanding the selectivity of genistein for human estrogen receptor-beta using X-ray crystallography and computational methods. Structure. 2004;12:2197–2207.
   PubMed Web of Science ®Google Scholar
• Weiss JF, Landauer MR. History and development of radiation-protective agents. Int J Radiat Biol. 2009;85:539–573.
   PubMed Web of Science ®Google Scholar
• Humanetics Pharmaceuticals. BIO 300 – A unique, highly selective radiation modulator. 2019 [cited 2020 Jan 3]. Available from: https://www.humaneticscorp.com/
   Google Scholar
• U.S. Food and Drug Administration. Guidance document: product development under the animal rule. 2015 [cited 2018 Oct 20]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm399217.pdf
   Google Scholar
• Singh VK, Newman VL, Romaine PL, et al. Use of biomarkers for assessing radiation injury and efficacy of countermeasures. Expert Rev Mol Diagn. 2016;16:65–81.
   PubMed Web of Science ®Google Scholar
• Pannkuk EL, Fornace AJ Jr., Laiakis EC. Metabolomic applications in radiation biodosimetry: exploring radiation effects through small molecules. Int J Radiat Biol. 2017;93:1151–1176.
   PubMed Web of Science ®Google Scholar
• Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31.
   PubMedGoogle Scholar
• Ye H, Shaw IC. Food flavonoid ligand structure/estrogen receptor-alpha affinity relationships - toxicity or food functionality? Food Chem Toxicol. 2019;129:328–336.
   PubMed Web of Science ®Google Scholar
• Nilsson S, Gustafsson JA. Estrogen receptors: therapies targeted to receptor subtypes. Clin Pharmacol Ther. 2011;89:44–55.
   PubMed Web of Science ®Google Scholar
• Heldring N, Pike A, Andersson S, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–931.
   PubMed Web of Science ®Google Scholar
• Warner M, Huang B, Gustafsson JA. Estrogen receptor beta as a pharmaceutical target. Trends Pharmacol Sci. 2017;38:92–99.
   PubMed Web of Science ®Google Scholar
• Weihua Z, Saji S, Makinen S, et al. Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus. Proc Natl Acad Sci USA. 2000;97:5936–5941.
   PubMed Web of Science ®Google Scholar
• Shim GJ, Wang L, Andersson S, et al. Disruption of the estrogen receptor beta gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis. Proc Natl Acad Sci USA. 2003;100:6694–6699.
   PubMed Web of Science ®Google Scholar
• Nakajima Y, Akaogi K, Suzuki T, et al. Estrogen regulates tumor growth through a nonclassical pathway that includes the transcription factors ERbeta and KLF5. Sci Signal. 2011;4:ra22.
   PubMed Web of Science ®Google Scholar
• Rizza P, Barone I, Zito D, et al. Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines. Breast Cancer Res. 2014;16:R21.
   PubMed Web of Science ®Google Scholar
• Mizukami Y. In vivo functions of GPR30/GPER-1, a membrane receptor for estrogen: from discovery to functions in vivo. Endocr J. 2010;57:101–107.
   PubMed Web of Science ®Google Scholar
• Prossnitz ER, Hathaway HJ. What have we learned about GPER function in physiology and disease from knockout mice? J Steroid Biochem Mol Biol. 2015;153:114–126.
   PubMed Web of Science ®Google Scholar
• Ignatov T, Modl S, Thulig M, et al. GPER-1 acts as a tumor suppressor in ovarian cancer. J Ovarian Res. 2013;6:51.
   PubMed Web of Science ®Google Scholar
• Martin SG, Lebot MN, Sukkarn B, et al. Low expression of G protein-coupled oestrogen receptor 1 (GPER) is associated with adverse survival of breast cancer patients. Oncotarget. 2018;9:25946–25956.
   PubMedGoogle Scholar
• Weissenborn C, Ignatov T, Ochel HJ, et al. GPER functions as a tumor suppressor in triple-negative breast cancer cells. J Cancer Res Clin Oncol. 2014;140:713–723.
   PubMed Web of Science ®Google Scholar
• Du ZR, Feng XQ, Li N, et al. G protein-coupled estrogen receptor is involved in the anti-inflammatory effects of genistein in microglia. Phytomedicine. 2018;43:11–20.
   PubMed Web of Science ®Google Scholar
• Liang S, Chen Z, Jiang G, et al. Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-kappaB/IL-6 signals. Cancer Lett. 2017;386:12–23.
   PubMed Web of Science ®Google Scholar
• Luo LJ, Liu F, Lin ZK, et al. Genistein regulates the IL-1 beta induced activation of MAPKs in human periodontal ligament cells through G protein-coupled receptor 30. Arch Biochem Biophys. 2012;522:9–16.
   PubMed Web of Science ®Google Scholar
• Vitale DC, Piazza C, Melilli B, et al. Isoflavones: estrogenic activity, biological effect and bioavailability. Eur J Drug Metab Pharmacokinet. 2013;38:15–25.
   PubMed Web of Science ®Google Scholar
• Kuiper GG, Lemmen JG, Carlsson B, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998;139:4252–4263.
   PubMed Web of Science ®Google Scholar
• Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: A potential novel mechanism of endocrine disruption. J Steroid Biochem Mol Biol. 2006;102:175–179.
   PubMed Web of Science ®Google Scholar
• Landauer MR, Harvey AJ, Kaytor MD, et al. Mechanism and therapeutic window of a genistein nanosuspension to protect against hematopoietic-acute radiation syndrome. J Radiat Res. 2019;60:308–317.
   PubMed Web of Science ®Google Scholar
• Si H, Liu D. Phytochemical genistein in the regulation of vascular function: new insights. Curr Med Chem. 2007;14:2581–2589.
   PubMed Web of Science ®Google Scholar
• Majid S, Kikuno N, Nelles J, et al. Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification. Cancer Res. 2008;68:2736–2744.
   PubMed Web of Science ®Google Scholar
• Frey RS, Li J, Singletary KW. Effects of genistein on cell proliferation and cell cycle arrest in nonneoplastic human mammary epithelial cells: involvement of Cdc2, p21(waf/cip1), p27(kip1), and Cdc25C expression. Biochem Pharmacol. 2001;61:979–989.
   PubMed Web of Science ®Google Scholar
• Ding H, Duan W, Zhu W-G, et al. p21 response to DNA damage induced by genistein and etoposide in human lung cancer cells. Biochem Biophys Res Commun. 2003;305:950–956.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Wang CZ, Du GJ, et al. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol. 2013;43:289–296.
   PubMed Web of Science ®Google Scholar
• Oki T, Sowa Y, Hirose T, et al. Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line. FEBS Lett. 2004;577:55–59.
   PubMed Web of Science ®Google Scholar
• La Rosa FA, Pierce JW, Sonenshein GE. Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors. Mol Cell Biol. 1994;14:1039–1044.
   PubMed Web of Science ®Google Scholar
• Gartel AL, Shchors K. Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. Exp Cell Res. 2003;283:17–21.
   PubMed Web of Science ®Google Scholar
• Su Y, Simmen RC. Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates beta-catenin signaling in mammary epithelial cells. Carcinogenesis. 2009;30:331–339.
   PubMed Web of Science ®Google Scholar
• Jagadeesh S, Kyo S, Banerjee PP. Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells. Cancer Res. 2006;66:2107–2115.
   PubMed Web of Science ®Google Scholar
• Zhu J, Ren J, Tang L. Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression. Mol Med Rep. 2018;17:7265–7273.
   PubMed Web of Science ®Google Scholar
• Zenk JL. New therapy for the prevention and prophylactic treatment of acute radiation syndrome. Expert Opin Investig Drugs. 2007;16:767–770.
   PubMed Web of Science ®Google Scholar
• Landauer, M.R. et al. Radioprotection by oral administration of genistein in mice receiving total body irradiation. 48th Annual Meeting and ToxExpo; March 15–19; Baltimore, MD. 2009.
   Google Scholar
• Landauer M. Radioprotection by the Soy Isoflavone Genistein. In: Arora R, editor. Herbal radiomodulators: applications in medicine, Homeland defense and space. Wallingford, England: CABI Publishing; 2008. p. 163–173.
   Google Scholar
• Singh VK, Seed TM. Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems. Expert Opin Pharmacother. 2020;21:317–337.
   PubMed Web of Science ®Google Scholar
• Landauer MR, Srinivasan V, Seed TM. Genistein treatment protects mice from ionizing radiation injury. J Appl Toxicol. 2003;23:379–385.
   PubMed Web of Science ®Google Scholar
• Davis TA, Clarke TK, Mog SR, et al. Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival. Int J Radiat Biol. 2007;83(3):141–151.
   PubMed Web of Science ®Google Scholar
• Ha CT, Li XH, Fu D, et al. Genistein nanoparticles protect mouse hematopoietic system and prevent proinflammatory factors after gamma irradiation. Radiat Res. 2013;180:316–325.
   PubMed Web of Science ®Google Scholar
• Davis TA, Mungunsukh O, Zins S, et al. Genistein induces radioprotection by hematopoietic stem cell quiescence. Int J Radiat Biol. 2008;84:713–726.
   PubMed Web of Science ®Google Scholar
• Day RM, Davis TA, Barshishat-Kupper M, et al. Enhanced hematopoietic protection from radiation by the combination of genistein and captopril. Int Immunopharmacol. 2013;15:348–356.
   PubMed Web of Science ®Google Scholar
• Day RM, Barshishat-Kupper M, Mog SR, et al. Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat Res. 2008;49:361–372.
   PubMed Web of Science ®Google Scholar
• Davis TA, Landauer MR, Mog SR, et al. Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation. Exp Hematol. 2010;38:270–281.
   PubMed Web of Science ®Google Scholar
• Dykstra JC, Harvey AJ, Ingram MAC, et al. Development of BIO 300 as a Medical Countermeasure for H-ARS and DEARE-lung. In Policies and Regulatory Pathways to FDA Licensure: Radiation Countermeasures and Biodosimetry Devices. Rockville, MD, USA: RNCP, NIAID; 2018
   Google Scholar
• Jackson DP, Sorensen DK, Cronkite EP, et al. Effectiveness of transfusions of fresh and lyophilized platelets in controlling bleeding due to thrombocytopenia. J Clin Invest. 1959;38:1689–1697.
   PubMed Web of Science ®Google Scholar
• Jackson IL, Vujaskovic Z, Down JD. Revisiting strain-related differences in radiation sensitivity of the mouse lung: recognizing and avoiding the confounding effects of pleural effusions. Radiat Res. 2010;173:10–20.
   PubMed Web of Science ®Google Scholar
• Jackson IL, Vujaskovic Z, Down JD. A further comparison of pathologies after thoracic irradiation among different mouse strains: finding the best preclinical model for evaluating therapies directed against radiation-induced lung damage. Radiat Res. 2011;175:510–518.
   PubMed Web of Science ®Google Scholar
• Jackson IL, Zodda A, Gurung G, et al. BIO 300, a nanosuspension of genistein, mitigates pneumonitis/fibrosis following high-dose radiation exposure in the C57L/J murine model. Br J Pharmacol. 2017;174:4738–4750.
   PubMed Web of Science ®Google Scholar
• Para AE, Bezjak A, Yeung IW, et al. Effects of genistein following fractionated lung irradiation in mice. Radiother Oncol. 2009;92:500–510.
   PubMed Web of Science ®Google Scholar
• Mahmood J, Jelveh S, Calveley V, et al. Mitigation of radiation-induced lung injury by genistein and EUK-207. Int J Radiat Biol. 2011;87:889–901.
   PubMed Web of Science ®Google Scholar
• Jackson IL, Pavlovic R, Alexander AA, et al. BIO 300, a nanosuspension of genistein, mitigates radiation-induced erectile dysfunction and sensitizes human prostate cancer xenografts to radiation therapy. Int J Radiat Oncol Biol Phys. 2019;105:400–409.
   PubMed Web of Science ®Google Scholar
• Brown SL, Kaytor MD, Lapanowski K, et al. BIO 300 (genistein oral nanosuspension) protects normal lung tissue and radiosensitizes tumor tissue in a mouse xenograft model of non-small cell lung cancer (NSCLC). In The 60th Annual Meeting of the Radiation Research Society; Las Vegas, NV; 2014.
   Google Scholar
• Ossetrova NI, Sandgren DJ, Blakely WF. Protein biomarkers for enhancement of radiation dose and injury assessment in nonhuman primate total-body irradiation model. Radiat Prot Dosimetry. 2014;159:61–76.
   PubMed Web of Science ®Google Scholar
• Ossetrova NI, Condliffe DP, Ney PH, et al. Early-response biomarkers for assessment of radiation exposure in a mouse total-body irradiation model. Health Phys. 2014;106(6):772–786.
   PubMed Web of Science ®Google Scholar
• Krivokrysenko VI, Shakhov AN, Singh VK, et al. Identification of granulocyte colony-stimulating factor and interleukin-6 as candidate biomarkers of CBLB502 efficacy as a medical radiation countermeasure. J Pharmacol Exp Ther. 2012;343:497–508.
   PubMed Web of Science ®Google Scholar
• Singh VK, Simas M, Pollard H. Biomarkers for acute radiation syndrome: challenges for developing radiation countermeasures following animal rule. Expert Rev Mol Diagn. 2018;18:921–924.
   PubMed Web of Science ®Google Scholar
• Singh VK, Santiago PT, Simas M, et al. Acute radiation syndrome: an update on biomarkers for radiation injury. J Radiat Cancer Res. 2019;9:132–146.
   Google Scholar
• Singh VK, Grace MB, Parekh VI, et al. Effects of genistein administration on cytokine induction in whole-body gamma irradiated mice. Int Immunopharmacol. 2009;9:1401–1410.
   PubMed Web of Science ®Google Scholar
• Kong FM, Ao X, Wang L, et al. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer Control. 2008;15:140–150.
   PubMedGoogle Scholar
• Allen TC, Kurdowska A. Interleukin 8 and acute lung injury. Arch Pathol Lab Med. 2014;138:266–269.
   PubMed Web of Science ®Google Scholar
• Jones JW, Jackson IL, Vujaskovic Z, et al. Targeted metabolomics identifies pharmacodynamic biomarkers for BIO 300 mitigation of radiation-induced lung injury. Pharm Res. 2017;34:2698–2709.
   PubMed Web of Science ®Google Scholar
• Cheema AK, Mehta KY, Santiago PT, et al. Pharmacokinetic and metabolomic studies with BIO 300, a nanosuspension of genistein, in a nonhuman primate model. Int J Mol Sci. 2019;20:1231.
   PubMed Web of Science ®Google Scholar
• Chang KL, Kung ML, Chow NH, et al. Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21waf1/cip1 and Wee1. Biochem Pharmacol. 2004;67:717–726.
   PubMed Web of Science ®Google Scholar
• Ye R, Bodero A, Zhou BB, et al. The plant isoflavenoid genistein activates p53 and Chk2 in an ATM-dependent manner. J Biol Chem. 2001;276:4828–4833.
   PubMed Web of Science ®Google Scholar
• Zhu J, Zhang C, Qing Y, et al. Genistein induces apoptosis by stabilizing intracellular p53 protein through an APE1-mediated pathway. Free Radic Biol Med. 2015;86:209–218.
   PubMed Web of Science ®Google Scholar
• Landauer, M.R. et al. Radioprotection by oral administration of genistein in mice receiving total body irradiation. 48th Annual Meeting and ToxExpo; March 15–19; Baltimore, MD. 2009.
   Google Scholar
• McClain RM, Wolz E, Davidovich A, et al. Reproductive safety studies with genistein in rats. Food Chem Toxicol. 2007;45:1319–1332.
   PubMed Web of Science ®Google Scholar
• McClain RM, Wolz E, Davidovich A, et al. Subchronic and chronic safety studies with genistein in dogs. Food Chem Toxicol. 2005;43:1461–1482.
   PubMed Web of Science ®Google Scholar
• McClain RM, Wolz E, Davidovich A, et al. Acute, subchronic and chronic safety studies with genistein in rats. Food Chem Toxicol. 2006;44:56–80.
   PubMed Web of Science ®Google Scholar
• Michael McClain R, Wolz E, Davidovich A, et al. Genetic toxicity studies with genistein. Food Chem Toxicol. 2006;44:42–55.
   PubMed Web of Science ®Google Scholar
• Ullmann U, Metzner J, Frank T, et al. Safety, tolerability, and pharmacokinetics of single ascending doses of synthetic genistein (Bonistein) in healthy volunteers. Adv Ther. 2005;22:65–78.
   PubMed Web of Science ®Google Scholar
• Ullmann U, Oberwittle H, Grossmann M, et al. Repeated oral once daily intake of increasing doses of the novel synthetic genistein product Bonistein in healthy volunteers. Planta Med. 2005;71:891–896.
   PubMed Web of Science ®Google Scholar
• Metzner JE, Frank T, Kunz I, et al. Study on the pharmacokinetics of synthetic genistein after multiple oral intake in post-menopausal women. Arzneimittelforschung. 2009;59:513–520.
   PubMed Web of Science ®Google Scholar
• Kim KH, Dodsworth C, Paras A, et al. High dose genistein aglycone therapy is safe in patients with mucopolysaccharidoses involving the central nervous system. Mol Genet Metab. 2013;109:382–385.
   PubMed Web of Science ®Google Scholar
• Busby MG, Jeffcoat AR, Bloedon LT, et al. Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. Am J Clin Nutr. 2002;75:126–136.
   PubMed Web of Science ®Google Scholar
• Fischer L, Mahoney C, Jeffcoat AR, et al. Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia. Nutr Cancer. 2004;48:160–170.
   PubMed Web of Science ®Google Scholar
• Bloedon LT, Jeffcoat AR, Lopaczynski W, et al. Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women. Am J Clin Nutr. 2002;76:1126–1137.
   PubMed Web of Science ®Google Scholar
• Tacyildiz N, Ozyoruk D, Yavuz G, et al. Soy isoflavones ameliorate the adverse effects of chemotherapy in children. Nutr Cancer. 2010;62:1001–1005.
   PubMed Web of Science ®Google Scholar
• Ahmad IU, Forman JD, Sarkar FH, et al. Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer. 2010;62:996–1000.
   PubMed Web of Science ®Google Scholar
• Kaytor MD, Brown SL, Arapi I, et al. A phase 1b/2a study evaluating the pharmacokinetics, safety, and efficacy of nano-genistein and chemoradiotherapy for non-small cell lung cancer. In Annual Meeting of the Amercian Society for Radiation Oncology; 2018 Oct 21–24; San Antonio, TX; 2018. p. E688.
   Google Scholar
• U. S. Food and Drug Administration. Search orphan drug designations and approvals. 2019 [cited 2020 Feb 5]. Available from: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/
   Google Scholar
• Singh VK, Pollard HB. Ionizing radiation-induced altered microRNA expression as biomarkers for assessing acute radiation injury. Expert Rev Mol Diagn. 2017;17:871–874.
   PubMed Web of Science ®Google Scholar