Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells.
We evaluated the use of colony formation (colony-forming unit-granulocyte macrophage [CFU-GM], burst-forming unit erythroid [BFU-E], and colony-forming unit-granulocyte-erythroid-megakaryocyte-monocytes [CFU-GEMM]) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. The following compounds were added before (protection) or after (mitigation) ionizing irradiation: GS-nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor LY29400, triphenylphosphonium-imidazole fatty acid, the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propranolol, and the adenosine triphosphate-sensitive potassium channel blocker (glyburide). The drugs XJB-5-131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU-GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs were effective in murine assays; TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide but showed no significant protection or mitigation in human CB assays. These data support the testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, thus reducing the need for animal experiments.
Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
Julie P
JP
Goff
Donna S
DS
Shields
Hong
H
Wang
Erin M
EM
Skoda
Melissa M
MM
Sprachman
Peter
P
Wipf
Venkata Krishna
VK
Garapati
Jeffrey
J
Atkinson
Barry
B
London
John S
JS
Lazo
Valerian
V
Kagan
Michael W
MW
Epperly
Joel S
JS
Greenberger
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D005312:Fetal Blood / Q000166:cytology*; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D009589:Nitrogen Oxides / Q000494:pharmacology; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012451:Safrole / Q000031:analogs & derivatives / Q000494:pharmacology
D003497:Cyclic N-Oxides; C544775:JP4-039; D009589:Nitrogen Oxides; D011837:Radiation-Protective Agents; C523959:XJB-5-131; D012451:Safrole; C005746:sulfoxide