Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors.
Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF. In the steady-state blood samples (before HD-CTX), megakaryocyte burst-forming units (BFU-Meg) and megakaryocyte colony-forming units (CFU-Meg) were virtually undetectable (< or = 1/mL BFU-Meg and CFU-Meg, range 0 to 1) by assaying unfractionated leukocytes. In contrast, in the recovery-phase blood samples (after HD-CTX), BFU-Meg and CFU-Meg increased several hundred-fold over steady-state values. This occurred regardless of the in vivo growth factors used and in parallel with increases in mixed, erythroid, and myeloid progenitors. In vitro, recovery-phase BFU-Meg and CFU-Meg responded to the novel GM-CSF/IL-3 fusion protein PIXY321 similarly as to optimal concentrations of rhIL-3 and rhGM-CSF. However, these progenitors differed from those in the steady state because BFU-Meg had faster duplication time and CFU-Meg prevailed numerically (CFU-Meg to BFU-Meg ratio 3.4 [recovery] vs. 0.52 [steady state]). Furthermore, soluble c-kit ligand/rh stem cell factor (rhSCF), in vitro in combination with rhIL-3 and rhGM-CSF or PIXY321, increased the size but not the number of colonies derived from recovery-phase BFU-Meg and CFU-Meg. These quantitative and qualitative changes occurring in circulating megakaryocyte progenitors contribute to the understanding of the rapid platelet recovery that occurs when peripheral blood hematopoietic progenitors elicited by HD-CTX and growth factor(s) are transplanted into patients treated with myeloablative chemoradiotherapy.
Siena
S
S
Cristina Gandini Unit, Istituto Nazionale Tumori, Milan, Italy.
Bregni
M
M
Bonsi
L
L
Sklenar
I
I
Bagnara
G P
GP
Bonadonna
G
G
Gianni
A M
AM
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001772:Blood Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology / Q000627:therapeutic use; D008533:Megakaryocytes / Q000166:cytology* / Q000276:immunology; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000494:pharmacology; D016184:Receptors, Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D019089:Stem Cell Factor; D013997:Time Factors
D015703:Antigens, CD; D018952:Antigens, CD34; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; C078524:PIXY321 fusion protein, recombinant; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases