Antiapoptotic cytokines in combination with pegfilgrastim soon after irradiation mitigates myelosuppression in nonhuman primates exposed to high irradiation dose.
OBJECTIVE
Preservation of hematopoietic stem and progenitor cells from early radiation-induced apoptosis is the rationale for emergency antiapoptotic cytokine therapy (EACK) after radiation accidents. This strategy is based on the combination of stem cell factor + Flt3-ligand + thrombopoietin + interleukin 3 (SFT3). The long-term safety and efficacy of EACK in managing severe radiation exposure were evaluated.


METHODS
Early administration of SFT3 + pegfilgrastim was assessed in 7-Gy gamma total body-irradiated (TBI) monkeys. Efficiency of delayed administration was also addressed after 5-Gy TBI.


RESULTS
Here we showed that a single, intravenous injection of SFT3 2 hours after 7-Gy TBI reduced the period of thrombocytopenia (platelet count <20 x 10(9)/L: 0.8 +/- 1.5 day vs 23.8 +/- 15.9 days in controls; p < 0.05) and blood transfusion needs. Moreover, addition of pegfilgrastim to SFT3 treatment shortened the period of neutropenia compared with SFT3 and control groups (neutrophil count <0.5 x 10(9)/L: 7 +/- 1.4 days vs 13 +/- 3.2 days and 15.2 +/- 1.5 days; p < 0.05). In both SFT3 groups, bone marrow activity recovered earlier and, in contrast with controls, platelet count returned to baseline values from 250 days after irradiation. Furthermore, delayed (48 hours) single SFT3 administration in 5-Gy irradiated monkeys significantly reduced thrombocytopenia compared to controls. Finally, SFT3 did not increase frequency of total chromosome translocations observed in the blood lymphocytes of controls 1 year after 5 Gy TBI.


CONCLUSIONS
These results suggest the safety and efficacy of EACK in managing severe radiation exposure.
Hérodin
Francis
F
Centre de Recherches du Service de Santé des Armées, la Tronche, France. Francis.Herodin@wanadoo.fr
Roy
Laurence
L
Grenier
Nancy
N
Delaunay
Christophe
C
Baugé
Stéphane
S
Vaurijoux
Aurélie
A
Grégoire
Eric
E
Martin
Cécile
C
Alonso
Antonia
A
Mayol
Jean-François
JF
Drouet
Michel
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001792:Blood Platelets / Q000187:drug effects / Q000528:radiation effects; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000528:radiation effects*; D016207:Cytokines / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects / Q000528:radiation effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008252:Macaca fascicularis; D008297:Male; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000494:pharmacology
D016207:Cytokines; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim