Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF.
The most important physiological regulator of megakaryocytopoiesis is the ligand for the c-mpl receptor (thrombopoietin/megakaryocyte growth and development factor, MGDF). We examined the effect of pegylated-recombinant human MGDF (PEG-rHuMGDF): patients received PEG-rHuMGDF at doses of 0.03, 0.1, 0.3 or 1.0 microg/kg/d or placebo for 10d maximum in a double-blinded randomized study. There was a dose-dependent elevation in circulating platelet counts but no alteration in erythrocyte or total leucocyte counts. The number of bone marrow megakaryocytes was increased approximately 2-fold. The frequency of bone marrow progenitor cells was not altered. In contrast, both to the bone marrow results and to published pre-clinical data, there was a dose-dependent mobilization into the blood of progenitor cells of multiple cell lineages. Increased levels of Meg-CFC (maximum increase 30-fold), day 7 and day 14 GM-CFC and BFU-E were demonstrated at doses of 0.3 and 1.0 microg/kg/d PEG-rHuMGDF. At 0.1 microg/kg/d, mobilization of Meg-CFC alone occurred in two-thirds of patients. Maximum blood levels of progenitor cells occurred at day 12. Thus, administration of PEG-rHuMGDF to humans resulted in mobilization of progenitor cells of multiple lineages despite its 'lineage-specific' activity on mature cell development.
Rasko
J E
JE
Centre for Developmental Cancer Therapeutics, Victoria, Australia.
Basser
R L
RL
Boyd
J
J
Mansfield
R
R
O'Malley
C J
CJ
Hussein
S
S
Berndt
M C
MC
Clarke
K
K
O'Byrne
J
J
Sheridan
W P
WP
Grigg
A P
AP
Begley
C G
CG
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000473:pathology; D019070:Cell Lineage; D048429:Cell Size; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects* / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000628:therapy; D010976:Platelet Count; D011518:Proto-Oncogene Proteins / Q000627:therapeutic use*; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin
D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human