Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid

Wenlin Deng, Yasuhiro Kimura, Veeresh Gududuru, Wenjie Wu, Andrea Balogh, Erzsebet Szabo, Karin Emmons Thompson, Charles Yates, Louisa Balazs, Leonard R. Johnson, Duane Miller, Jur Strobos, W. Shannon McCool, Gabor Tigyi

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)465-475
Number of pages11
JournalRadiation Research
Volume183
Issue number4
DOIs
StatePublished - Apr 1 2015

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Acute Radiation Syndrome
mice
mortality
dosage
acids
irradiation
Whole-Body Irradiation
radiation
molecules
endotoxins
seepage
leukocytes
Lethal Dose 50
platelets
glucose
blood
Mortality
margins
safety
Radiation Dosage

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

Cite this

Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid. / Deng, Wenlin; Kimura, Yasuhiro; Gududuru, Veeresh; Wu, Wenjie; Balogh, Andrea; Szabo, Erzsebet; Thompson, Karin Emmons; Yates, Charles; Balazs, Louisa; Johnson, Leonard R.; Miller, Duane; Strobos, Jur; McCool, W. Shannon; Tigyi, Gabor.

In: Radiation Research, Vol. 183, No. 4, 01.04.2015, p. 465-475.

Research output: Contribution to journalArticle

Deng, Wenlin ; Kimura, Yasuhiro ; Gududuru, Veeresh ; Wu, Wenjie ; Balogh, Andrea ; Szabo, Erzsebet ; Thompson, Karin Emmons ; Yates, Charles ; Balazs, Louisa ; Johnson, Leonard R. ; Miller, Duane ; Strobos, Jur ; McCool, W. Shannon ; Tigyi, Gabor. / Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid. In: Radiation Research. 2015 ; Vol. 183, No. 4. pp. 465-475.
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