TY - JOUR
T1 - A schedule of recombinant Mpl ligand highly effective at preventing lethal myelosuppression in mice given carboplatin and radiation
AU - Abushullaih, Basel A.
AU - Pestina, Tamara I.
AU - Srivastava, Deo Kumar
AU - Jackson, Carl W.
AU - Daw, Najat C.
N1 - Funding Information:
Supported in part by grants P30CA21765 and P01CA20180 from the National Cancer Institute, U.S. Public Health Service, the Department of Health and Human Services, and by the American Lebanese Syrian Associated Charities (ALSAC). The authors thank Deepthi Jayawardene for assistance with statistical analysis, Sharon Naron for scientific editing, Kerry Roberts for secretarial assistance, and Amgen, Inc. for their generous supply of PEG-rmMGDF.
PY - 2001
Y1 - 2001
N2 - ObjectiveTo determine a thrombopoietin schedule that would effectively enhance hematopoiesis and prevent death in mice after lethal myelosuppression.MethodsFirst, 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).ResultsIn 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.ConclusionMpl-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.
AB - ObjectiveTo determine a thrombopoietin schedule that would effectively enhance hematopoiesis and prevent death in mice after lethal myelosuppression.MethodsFirst, 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).ResultsIn 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.ConclusionMpl-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.
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U2 - 10.1016/S0301-472X(01)00748-2
DO - 10.1016/S0301-472X(01)00748-2
M3 - Article
C2 - 11750101
AN - SCOPUS:0035652689
SN - 0301-472X
VL - 29
SP - 1425
EP - 1431
JO - Experimental Hematology
JF - Experimental Hematology
IS - 12
ER -