title: Serum FLT-3 ligand in a busulphan-induced model of chronic bone marrow hypoplasia in the female CD-1 mouse.
abstract: The concentration of the cytokine fms-like tyrosine kinase-3 ligand (FL) is elevated in the plasma of patients treated with chemotherapy or radiotherapy for malignant conditions. In addition, plasma FL is increased in patients with bone marrow failure resulting from stem-cell defects (e.g. aplastic anaemia). Our goal in the present study was to measure the concentration of serum FL in mice treated with the chemotherapeutic agent busulphan (BU) to induce bone marrow depression and relate changes in FL to effects on haemopoiesis. Female CD-1 mice were treated with BU (9.0 mg/kg) or vehicle by intraperitoneal injection on 10 occasions over 21 days. Animals were autopsied on days 1, 23, 72, 119 and 177 postdosing. A full blood count was performed, and serum prepared for FL analysis. Femoral marrow cell suspensions were prepared to assess the total femoral nucleated cell count (FNCC) and the number of committed haemopoietic progenitor cells (CFU-C). On days 1 and 23 postdosing, significant decreases were evident in many peripheral blood parameters; the FNCC and CFU-C were also reduced in BU-treated mice, in conjunction with increases in serum FL levels. On days 72, 119 and 177 postdosing, several peripheral blood and bone marrow parameters remained reduced and the concentration of serum FL continued to be significantly increased. Linear regression analysis demonstrated significant correlations between the concentration of serum FL in BU-treated mice and peripheral blood and bone marrow parameters; this suggests the possible use of serum FL as a potential biomarker for drug-induced bone marrow injury.
authors.affiliation: Division of Cellular and Molecular Medicine, Section for Cellular and Molecular Pathology, St. George's, University of London, London, UK. gemma.molyneux@icr.ac.uk
authors.forename: Gemma
authors.initials: G
authors.lastname: Molyneux
authors.forename: Frances M
authors.initials: FM
authors.lastname: Gibson
authors.forename: Matthew
authors.initials: M
authors.lastname: Whayman
authors.forename: John A
authors.initials: JA
authors.lastname: Turton
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D002066:Busulfan / Q000633:toxicity*; D002908:Chronic Disease; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008565:Membrane Proteins / Q000097:blood*; D051379:Mice; D010198:Pancytopenia / Q000097:blood / Q000139:chemically induced
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C084881:flt3 ligand protein; D002066:Busulfan