Preclinical studies and potential clinical applications of c-mpl ligand.
The cloning of the gene for the endogenous c-mpl ligand, also known as thrombopoietin, was first reported less than 2 years ago. Recombinant mpl ligands based on this gene have been extensively evaluated in preclinical studies and are now in the early stages of clinical development. In vivo studies have confirmed that c-mpl ligand is a lineage-dominant cytokine and is the primary physiologic regulator of megakaryocytopoiesis. Recombinant mpl ligands can substantially reduce the severity and duration of thrombocytopenia due to myelosuppressive irradiation, chemotherapy, or both. Moreover, when recombinant mpl ligand is used in combination with r-metHuG-CSF, both thrombocytopenia and neutropenia can be prevented to the same degree as with either cytokine alone. In normal animals, the platelets produced in response to recombinant mpl ligand function appropriately and should not pose an undue risk for thrombosis when administered to thrombocytopenic patients. Initial clinical data confirm the safety and biologic activity of these new agents in humans. Clinical development will likely target the most myelosuppressive regimens, including those used in hematopoietic cell transplantation and acute myelocytic leukemia. Ultimately, the clinical benefit of these drugs will likely be judged on their ability to reduce the duration of severe thrombocytopenia and the need for platelet transfusions.
Stead
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RB
Amgen, Thousand Oaks, CA 91320-1789, USA.
Harker
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LA
D000818:Animals; D003001:Cloning, Molecular; D006410:Hematopoiesis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D013926:Thrombopoietin / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use
D011994:Recombinant Proteins; D013926:Thrombopoietin