title: Further development of a model of chronic bone marrow aplasia in the busulphan-treated mouse.
abstract: Aplastic anaemia (AA) in man is an often fatal disease characterized by pancytopenia of the peripheral blood and aplasia of the bone marrow. AA is a toxic effect of many drugs and chemicals (e.g. chloramphenicol, azathioprine, phenylbutazone, gold salts, penicillamine and benzene). However, there are no widely used or convenient animal models of drug-induced AA. Recently, we reported a new model of chronic bone marrow aplasia (CBMA = AA) in the busulphan (BU)-treated mouse: eight doses of BU (10.50 mg/kg) were administered to female BALB/c mice over a period of 23 days; CBMA was evident at day 91/112 post-dosing with significantly reduced erythrocytes, platelets, leucocytes and nucleated bone marrow cell counts. However, mortality was high (49.3%). We have now carried out a study to modify the BU-dosing regime to induce CBMA without high mortality, and investigated the patterns of cellular responses in the blood and marrow in the post-dosing period. Mice (n = 64/65) were dosed 10 times with BU at 0 (vehicle control), 8.25, 9.0 and 9.75 mg/kg over 21 days and autopsied at day 1, 23, 42, 71, 84, 106 and 127 post-dosing (n = 7-15); blood and marrow samples were examined. BU induced a predictable bone marrow depression at day 1 post-dosing; at day 23/42 post-dosing, parameters were returning towards normal during a period of recovery. At day 71, 84, 106 and 127 post-dosing, a stabilized, late-stage, nondose-related CBMA was evident in BU-treated mice, with decreased erythrocytes, platelets and marrow cell counts, and increased MCV. At day 127 post-dosing, five BU-treated mice showed evidence of lymphoma. In this study, mortality was low, ranging from 3.1% (8.25 mg/kg BU) to 12.3% (9.75 mg/kg BU). It is concluded that BU at 9.0 mg/kg (or 9.25 mg/kg) is an appropriate dose level to administer (10 times over 21 days) to induce CBMA at approximately day 50-120 post-dosing.
authors.affiliation: Centre for Toxicology, Department of Pharmacology, School of Pharmacy, University of London, London, UK. john.turton@ulsop.ac.uk
authors.forename: John A
authors.initials: JA
authors.lastname: Turton
authors.forename: William R
authors.initials: WR
authors.lastname: Sones
authors.forename: Charles M
authors.initials: CM
authors.lastname: Andrews
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Pilling
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Williams
authors.forename: Gemma
authors.initials: G
authors.lastname: Molyneux
authors.forename: Sian
authors.initials: S
authors.lastname: Rizzo
authors.forename: Edward C
authors.initials: EC
authors.lastname: Gordon-Smith
authors.forename: Frances M
authors.initials: FM
authors.lastname: Gibson
mesh_terms: D000741:Anemia, Aplastic / Q000401:mortality / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D002066:Busulfan; D004305:Dose-Response Relationship, Drug; D005260:Female; D008223:Lymphoma / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D019653:Myeloablative Agonists; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013160:Splenic Neoplasms / Q000139:chemically induced / Q000473:pathology; D013194:Staining and Labeling; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000473:pathology
chemical_list: D019653:Myeloablative Agonists; D002066:Busulfan