Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice.
Megakaryocyte growth and development factor (MGDF) is a potent inducer of megakaryopoiesis in vitro and thrombopoiesis in vivo. The effects of MGDF appear to be lineage-selective, making this cytokine an ideal candidate for use in alleviating clinically relevant thrombocytopenias. This report describes a murine model of life-threatening thrombocytopenia that results from the combination treatment of carboplatin and sublethal irradiation. Mortality of this regimen is 94% and is associated with widespread internal bleeding. The daily administration of pegylated recombinant human MGDF (PEG-rMGDF) significantly reduced mortality (to < 15%) and ameliorated the depth and duration of thrombocytopenia. The severity of leucopenia and anemia was also reduced, although it was not clear whether these effects were direct. Platelets generated in response to PEG-rMGDF were morphologically indistinguishable from normal platelets. PEG-rMGDF administered in combination with murine granulocyte colony-stimulating factor completely prevented mortality and further reduced leukopenia and thrombocytopenia. These data support the concept that PEG-rMGDF may be useful to treat iatrogenic thrombocytopenias.
Amgen, Inc, Amgen Center, Thousand Oaks, CA 91320, USA.
M M
MM
Hokom
D
D
Lacey
O B
OB
Kinstler
E
E
Choi
S
S
Kaufman
J
J
Faust
C
C
Rowan
E
E
Dwyer
J L
JL
Nichol
T
T
Grasel
J
J
Wilson
R
R
Steinbrink
R
R
Hecht
D
D
Winters
T
T
Boone
P
P
Hunt
D000818:Animals; D016190:Carboplatin / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007970:Leukopenia / Q000209:etiology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010976:Platelet Count; D011092:Polyethylene Glycols; D011833:Radiation Injuries, Experimental / Q000150:complications*; D011994:Recombinant Proteins / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control*; D013926:Thrombopoietin / Q000737:chemistry / Q000627:therapeutic use*
D007155:Immunologic Factors; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin; D016190:Carboplatin