title: Early suppressive effects of chemotherapy on recovery of bone marrow megakaryocyte precursors: possible relationship to platelet recovery.
abstract: This study utilized a recently developed culture and quantitation system to detect megakaryocyte precursors in CD34+ bone marrow cells from normal donors and breast cancer patients treated with 5-fluorouracil, leucovorin, adriamycin and cyclophosphamide (FLAC). Bone marrow was obtained from patients before and then after their first cycle of FLAC once blood cell counts had recovered. CD34+ cells were isolated and placed in liquid culture with growth factors to stimulate proliferation and lineage commitment. Absorbance values from an enzyme-linked immunosorbent assay were used to quantitate expression of platelet glycoprotein GPIIb/IIIa. There was an increase in absorbance with increasing numbers of cells seeded per culture that was associated with an increase in the number of megakaryocyte lineage cells produced. After 10 days in liquid culture, absorbance values for expression of GPIIb/IIIa from 2,000 normal donor and pre-chemotherapy CD34+ marrow cells were > or = 1.0. Absorbance values from cultures of post-chemotherapy CD34+ cells from four patients were similar to values from pre-chemotherapy CD34+ cells. In contrast, absorbance values from cultures of post-chemotherapy CD34+ cells from two other patients were low (absorbance < 0.5). Low absorbance values for GPIIb/IIIa expression indicate that megakaryocyte production from those CD34+ cells was reduced. Both of those patients developed prolonged thrombocytopenia and platelet nadirs of less than 20,000/microl during FLAC chemotherapy. In contrast, only one out of four patients whose cultures of post-chemotherapy CD34+ cells had absorbance values > or = 1.0 developed platelet nadirs less than 20,000/microl. These results suggest that low platelet nadirs and delayed platelet recovery may be associated with suppressive effects of chemotherapy on recovery of megakaryocyte precursors.
authors.affiliation: Poietic Technologies, Germantown, Maryland, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Warren
authors.forename: J
authors.initials: J
authors.lastname: Zujewski
authors.forename: W L
authors.initials: WL
authors.lastname: Rose
authors.forename: J M
authors.initials: JM
authors.lastname: Szabo
authors.forename: J A
authors.initials: JA
authors.lastname: O'Shaughnessy
authors.forename: D C
authors.initials: DC
authors.lastname: Halverson
authors.forename: K H
authors.initials: KH
authors.lastname: Cowan
authors.forename: R E
authors.initials: RE
authors.lastname: Gress
authors.forename: G N
authors.initials: GN
authors.lastname: Schwartz
mesh_terms: D018952:Antigens, CD34 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001772:Blood Cell Count; D001792:Blood Platelets / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D016022:Case-Control Studies; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D002955:Leucovorin / Q000627:therapeutic use; D008533:Megakaryocytes / Q000378:metabolism / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000378:metabolism; D013921:Thrombocytopenia / Q000209:etiology; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D007377:Interleukin-3; C078524:PIXY321 fusion protein, recombinant; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D002955:Leucovorin; D005472:Fluorouracil