title: An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo.
abstract: An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p<0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p=0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50-400%. In sub-lethally-irradiated mice, ANC nadir remained >200/mm3and neutropenia recovered in 6days with ST7 treatment and 18days in controls (p<0.05). In lethally-irradiated mice, marrow pathology at 15days was hypocellular (10% cellularity) in controls, but normal (55-75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p<0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias.
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, MA, United States; Phoenicia BioSciences, Inc., Weston, MA, United States.
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Serguei A
authors.initials: SA
authors.lastname: Castaneda
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas Medical School, Little Rock, AR, United States.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Armed Forces Radiobiology Research Institute, Bethesda, MD, United States.
authors.forename: Merriline
authors.initials: M
authors.lastname: Vedamony
authors.affiliation: Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, United States.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Newburger
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
authors.forename: Gary L
authors.initials: GL
authors.lastname: White
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
authors.forename: Stanley
authors.initials: S
authors.lastname: Kosanke
authors.affiliation: Indiana University, Indianapolis, IN, United States.
authors.forename: P Artur
authors.initials: PA
authors.lastname: Plett
authors.affiliation: Indiana University, Indianapolis, IN, United States.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Boosalis
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, MA, United States; Phoenicia BioSciences, Inc., Weston, MA, United States. Electronic address: sperrine@bu.edu.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
mesh_terms: D000818:Animals; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000528:radiation effects; D009504:Neutrophils / Q000187:drug effects* / Q000528:radiation effects; D010215:Papio; D010666:Phenylpropionates / Q000494:pharmacology / Q000627:therapeutic use*; D000069079:Radiation Exposure / Q000009:adverse effects; D020127:Recovery of Function / Q000187:drug effects*; D015996:Survival Rate; D014916:Whole-Body Irradiation / Q000009:adverse effects* / Q000401:mortality
chemical_list: D010666:Phenylpropionates; C470568:alpha-methylhydrocinnamic acid