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
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 (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.