title: Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid.
abstract: We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy γ radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from -24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from -12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by ≥34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4-8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome.
authors: a  RxBio Inc., Memphis, Tennessee 38104;
authors: Wenlin
authors: W
authors: Deng
authors: Yasuhiro
authors: Y
authors: Kimura
authors: Veeresh
authors: V
authors: Gududuru
authors: Wenjie
authors: W
authors: Wu
authors: Andrea
authors: A
authors: Balogh
authors: Erzsebet
authors: E
authors: Szabo
authors: Karin Emmons
authors: KE
authors: Thompson
authors: C Ryan
authors: CR
authors: Yates
authors: Louisa
authors: L
authors: Balazs
authors: Leonard R
authors: LR
authors: Johnson
authors: Duane D
authors: DD
authors: Miller
authors: Jur
authors: J
authors: Strobos
authors: W Shannon
authors: WS
authors: McCool
authors: Gabor J
authors: GJ
authors: Tigyi
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D054508:Acute Radiation Syndrome / Q000517:prevention & control*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000528:radiation effects; D040761:Biomimetic Materials / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000528:radiation effects*; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D007958:Leukocyte Count; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010976:Platelet Count; D046988:Proteasome Endopeptidase Complex; D011837:Radiation-Protective Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D060588:LIM Domain Proteins; D008246:Lysophospholipids; D009943:Organophosphorus Compounds; C092282:PSMC5 protein, human; D010750:Phosphoproteins; D011837:Radiation-Protective Agents; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors; C520653:octadecenyl thiophosphate; C093376:sodium-hydrogen exchanger regulatory factor; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; D005947:Glucose; C032881:lysophosphatidic acid