PEG-rHuMGDF ameliorates thrombocytopenia in carboplatin-treated rats without inducing myelofibrosis.
We examined the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on carboplatin-induced thrombocytopenia in rats. The focus was on whether myelofibrosis is associated with the PEG-rHuMGDF treatment in this chemotherapy model. After a single injection of carboplatin, rats received subcutaneous PEG-rHuMGDF at pharmacologic doses (1,3, or 30 micrograms/kg) or a vehicle daily for 7 days. PEG-rHuMGDF at more than 3 micrograms/kg ameliorated the thrombocytopenia at day 10. Histologically, no myelofibrosis was detected in the rats treated with PEG-rHuMGDF or vehicle. Subsequently, PEG-rHuMGDF at a suprapharmacologic dose (100 micrograms/kg) was subcutaneously administered to normal and to carboplatin-treated rats daily for 7 days. Histological analysis revealed that the treatment with PEG-rHuMGDF induced myelofibrosis in the normal rats but not in the carboplatin-treated rats. Additionally, the transforming growth factor-beta 1 (TGF-beta 1) levels in the extracellular fluid and the whole extract of the bone marrow were increased to a much lesser degree in the carboplatin-treated rats compared to the normal rats. These findings suggest that PEG-rHuMGDF is effective for carboplatin-induced thrombocytopenia. Proper control of platelet counts and TGF-beta 1 levels is essential so that myelofibrosis is not induced in clinical use.
Ide
Y
Y
Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan. y-ide@kirin.co.jp
Harada
K
K
Imai
A
A
Yanagida
M
M
D000818:Animals; D000970:Antineoplastic Agents; D016190:Carboplatin; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects*; D055728:Primary Myelofibrosis / Q000139:chemically induced; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000188:drug therapy*; D013926:Thrombopoietin / Q000008:administration & dosage* / Q000009:adverse effects*
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin; D016190:Carboplatin