A schedule of recombinant Mpl ligand highly effective at preventing lethal myelosuppression in mice given carboplatin and radiation.
OBJECTIVE
To determine a thrombopoietin schedule that would effectively enhance hematopoiesis and prevent death in mice after lethal myelosuppression.


METHODS
First, we determined whether recombinant Mpl ligand (Mpl-L) has a priming effect on thrombopoiesis in normal mice. Mice were given pegylated recombinant murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF) intravenously as a single injection or as two injections separated by intervals of 1 to 10 days. Second, we examined the scheduling of PEG-rmMGDF that would most effectively reduce thrombocytopenia in mice given a lethal myelosuppressive regimen (80 mg/kg carboplatin + 750 R Cs-137 total-body irradiation).


RESULTS
In normal mice, peak platelet count with a 4-day to 8-day interval between PEG-rmMGDF injections was significantly higher than that with single injection. This priming effect was optimal with a 4-day interval between injections. In the lethal myelosuppression model, all mice given intravenous PEG-rmMGDF as a single injection on day 0 or as two injections (on days -4 and 0 or on days 0 and 4) survived; PEG-rmMGDF on day 0 was given immediately after the myelosuppressive regimen. In contrast, all mice given a single intravenous PEG-rmMGDF injection on day -4 or day 4 died. Two PEG-rmMGDF injections given on days -4 and 0 enhanced hematopoietic recovery more than did a single injection on day 0 or two injections on days 0 and 4.


CONCLUSIONS
Mpl-L administration immediately after lethal carboplatin and radiation prevents death and enhances hematopoietic recovery in mice; this protective effect is further enhanced by a priming Mpl-L dose given 4 days before the myelosuppressive regimen.
Abushullaih
B A
BA
Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, Tenn., USA.
Pestina
T I
TI
Srivastava
D K
DK
Jackson
C W
CW
Daw
N C
NC
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D016190:Carboplatin / Q000494:pharmacology*; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology*; D013997:Time Factors; D014916:Whole-Body Irradiation
D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin; D016190:Carboplatin