Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice.
Megakaryocyte growth and development factor (MGDF) administered intraperitoneally (IP) to mice causes a dose-dependent thrombocytosis accompanied by a decrease in mean platelet volume. MGDF increases the number of megakaryocytes in the bone marrow and spleen. MGDF does not affect the circulating number of leukocytes. Carboplatin, a chemotherapeutic agent that causes thrombocytopenia in humans, administered to mice as a single IP injection at a nonlethal dose causes a significant, but reversible thrombocytopenia. The carboplatin-induced thrombocytopenia is accompanied by an increase in circulating endogenous MGDF that precedes the return of circulating platelets to a normal level. MGDF mRNA is constitutively present in the liver. After carboplatin treatment, hepatic MGDF mRNA does not increase in concordance with circulating MGDF. Circulating soluble MGDF receptor levels (c-mpl) do not change significantly during the course of carboplatin-induced thrombocytopenia. MGDF injected IP once daily beginning 1 day after injection of carboplatin reverses carboplatin-induced thrombocytopenia in a dose-dependent fashion. The normalization of circulating platelet numbers in carboplatin plus MGDF-treated mice is accompanied by a normalization of megakaryocyte numbers in the bone marrow. In conclusion, MGDF, by increasing the number of marrow megakaryocytes and circulating platelets is an effective therapy for carboplatin-induced thrombocytopenia in mice.
Ulich
T R
TR
Amgen Inc., Thousand Oaks, CA 91320, USA.
del Castillo
J
J
Yin
S
S
Swift
S
S
Padilla
D
D
Senaldi
G
G
Bennett
L
L
Shutter
J
J
Bogenberger
J
J
Sun
D
D
D000818:Animals; D001854:Bone Marrow Cells; D016190:Carboplatin / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins; D013921:Thrombocytopenia / Q000188:drug therapy*; D013926:Thrombopoietin / Q000627:therapeutic use*
D011994:Recombinant Proteins; D013926:Thrombopoietin; D016190:Carboplatin