title: Induction of TGF-β by Irradiation or Chemotherapy in Fanconi Anemia (FA) Mouse Bone Marrow Is Modulated by Small Molecule Radiation Mitigators JP4-039 and MMS350.
abstract: Total-body irradiation and/or administration of chemotherapy drugs in bone marrow transplantation induce cytokines that can suppress engraftment. Fanconi Anemia (FA) patients have a hyperactive responsiveness to the inhibitory cytokine, transforming growth factor-beta (TGF-β). Small molecule radiation mitigator drugs, JP4-039 and MMS350, were evaluated for suppression of irradiation or drug-induced TGF-β.
  
  
  
  In vivo induction of TGF-β by total-body ionizing irradiation (TBI), L-phenylalanine mustard (L-PAM), busulfan or fludarabine, was quantified. In parallel, mitigator drug amelioration of TGF-β induction in FA D2-/-(FANCD2-/-) mouse bone marrow, was studied in vitro. Tissue culture medium, cell lysates, and mouse plasma were analyzed for TGF-β levels.
  
  
  
  Induction of TGF-β levels in FANCD2-/-and FANCD2+/+mice and in mouse bone marrow were modulated by both JP4-039 and MMS350.
  
  
  
  Bone marrow transplantation in FA recipients may benefit from administration of small molecule agents that suppress TGF-β induction.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Byung-Han
authors.initials: BH
authors.lastname: Rhieu
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Darcy
authors.initials: D
authors.lastname: Franicola
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Shaonan
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Xichen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Donna
authors.initials: D
authors.lastname: Shields
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, U.S.A.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A. greenbergerjs@upmc.edu.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002066:Busulfan / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004358:Drug Therapy / Q000379:methods; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D008558:Melphalan / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019653:Myeloablative Agonists / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D014916:Whole-Body Irradiation / Q000379:methods
chemical_list: D004988:Ethers, Cyclic; C544775:JP4-039; C586473:MMS350; D019653:Myeloablative Agonists; D009589:Nitrogen Oxides; D011837:Radiation-Protective Agents; D013454:Sulfoxides; D016212:Transforming Growth Factor beta; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D008558:Melphalan
keywords: Fanconi Anemia; JP4-039; MMS350; TGF-β; chemotherapy drugs; mitigators; molecular radiation; mouse bone marrow; total body irradiation