Radioprotective Effects of ON 01210.Na upon Oral Administration

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  • SUMAN Shubhankar
    Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University
  • DATTA Kamal
    Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University
  • DOIRON Kathryn
    Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University
  • REN Chen
    Onconova Therapeutics Inc.
  • KUMAR Ramesh
    Onconova Therapeutics Inc.
  • TAFT David R.
    Arnold & Marie Schwartz College of Pharmacy, Long Island University
  • FORNACE Jr. Albert J.
    Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University
  • MANIAR Manoj
    Onconova Therapeutics Inc.

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ON 01210.Na (Ex-RAD), a chlorobenzylsulfone derivative was investigated for its pharmacologic and radioprotective properties when administered via oral and subcutaneous (SC) routes. The goals of the study were to assess the comparative bioavailability of ON 01210.Na when administered by oral versus SC routes and to demonstrate that the oral drug delivery of ON 01210.Na afforded survival advantage similar to SC dosing. Pharmacokinetics was studied after two doses, 24 h apart, of ON 01210.Na (500 mg/kg) administered to male C3H/Hen mice (7–9 weeks) via SC injection or oral route. The dose response (100 to 750 mg/kg) and survival advantage of ON 01210.Na administered at 24 h and 15 min prior to 7.5 or 8 Gy whole body irradiation from a 137Cs source (dose rate 1 Gy/min) were studied in these mice. Effects on the hematopoietic system were investigated by complete blood count and granulocyte-macrophage colony forming unit assay. A significant survival advantage and hematopoietic protection were observed after prophylactic oral ON 01210.Na and results were comparable to SC administration. These findings correlated well with pharmacokinetic data. Both SC and oral ON 01210.Na showed significant survival advantage against radiation toxicity and ON 01210.Na mediated hematopoietic protection plays key role in enhanced survival of mice. Oral administration holds better clinical promise as an effective countermeasure not only for early-responders in a nuclear accident, but also for the at-risk civilian population.

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