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a Department of Experimental Transplantation and Immunology, Medicine Branch and
b Surgery Branch, National Cancer Institute, Bethesda, Maryland, USA;
c Poietic Technologies, Inc., Gaithersburg, Maryland, USA;
d Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
Key Words. Quantitative RT-PCR • Marrow stromal layers • Microenvironment • TaqMan • Chemokines • Thrombopoietin • Insulin-like growth factors
Gretchen N. Schwartz, Ph.D., Building 10, Room 12N226, Department of Experimental Transplantation and Immunology, Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. Telephone: 301-435-8641; Fax: 301-402-0172; e-mail: gnschwar{at}cpcug.org
CD34+ cells and megakaryocyte progenitors were lower in marrow from patients after hematological recovery from the first cycle of 5-fluorouracil, leucovorin, adriamycin, cyclophosphamide (FLAC) chemotherapy plus PIXY321 (GM-CSF/interleukin 3; IL-3 hybrid) than in FLAC + GM-CSF or pre-FLAC marrows. Marrow stromal layers, an in vitro model of the marrow microenvironment, express a combination of stimulatory and inhibitory factors that modulate hematopoietic progenitor cell proliferation and differentiation. The TaqMan assay and quantitative reverse transcriptase-polymerase chain reaction were used to measure monocyte chemoattractant protein-1 (MCP-1), melanoma stimulatory growth activity, and monokine inducible by interferon-
(Mig) (inhibitory chemokines for primitive or megakaryocyte progenitors) mRNA levels in in vitro PIXY and GM-CSF-treated and patient post-FLAC marrow stromal layers. Chemokine mRNA was increased after in vitro GM-CSF and to a lesser extent after PIXY treatment. MCP-1 mRNA levels were fivefold higher in FLAC + PIXY than in FLAC + GM-CSF layers, and Mig mRNA was elevated in FLAC + GM-CSF layers. Thrombopoietin (TPO), insulin-like growth factor I (IGF-I), and IGF-II (stimulatory factors for primitive and megakaryocyte progenitors) mRNA were also measured. TPO mRNA levels were 30% lower in GM-CSF and PIXY-pretreated than in control layers with no decrease in IGF mRNA. TPO mRNA in stromal layers of patients who developed grade 3 thrombocytopenia (platelets < 20 x 109/l) during the third cycle of FLAC was only 24% of levels in stromal layers of marrow from other post-FLAC patients. Results demonstrate that patient and in vitro treatment had modulatory effects on TPO and chemokine mRNA expression in marrow stromal layers.
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