NASHVILLE--In the last year, at least four groups have reported cloning proteins that appear to be the long-elusive megakaryocyte colony-stimulating growth factor thrombopoietin, which acts via the mpl cell surface receptor.
Laboratory studies have shown that thrombopoietin appears to have both early- and late-acting effects on the mega-karyocytic lineage. It results in increases in the number, size, and ploidy of mega-karyocyte colonies in bone marrow and has a potent effect on megakaryocyte maturation, leading to increased numbers of circulating platelets.
In a study presented at the scientific sessions of the American Society of Hematology (ASH) meeting, use of a recombinant mouse thrombopoietin developed by ZymoGenetics, Inc. (Seattle) was shown to stimulate recovery of platelets and, unexpectedly, red blood cells in myelosuppressed mice.
"These results indicate that cells able to respond to the growth factor are present in the marrow after cytoreductive therapy . . . and suggest that thrombopoietin may be useful clinically in speeding the recovery of both megakaryocytic and erythroid lineages in states of marrow failure," Katherine Sprugel, PhD, director of preclinical studies at ZymoGenetics, said in her presentation.
Initial studies to determine effective doses found that 25,000 units/day produced circulating platelet levels in normal mice more than fourfold greater than baseline, but the effect dropped off at higher doses, suggesting that the dose-response curve may be bell-shaped, Dr. Sprugel said. After treatment was stopped, platelet counts returned to normal within 7 to 10 days.
Despite the high circulating platelet counts, no overt toxicity was seen in any of the mice, and histopathology evaluation at the end of the study was unremarkable, she said.
To test the effectiveness of the agent, a myelosuppressed rodent model was required, and Dr. Sprugel's group used a model developed at Genetics Institute (Cambridge, Mass). These mice were exposed to single doses of sublethal total body irradiation and a single injection of carboplatin(Drug information on carboplatin) (Paraplatin). Starting 24 hours later, the mice received daily intraperitoneal injections of vehicle or thrombopoietin (25,000 or 75,000 units/day) for 18 days.