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Further development of a model of chronic bone marrow aplasia in the busulphan‐treated mouse
Author(s) -
Turton John A.,
Sones William R.,
Andrews Charles M.,
Pilling Andrew M.,
Williams Thomas C.,
Molyneux Gemma,
Rizzo Sian,
GordonSmith Edward C.,
Gibson Frances M.
Publication year - 2006
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.0959-9673.2006.00455.x
Subject(s) - bone marrow aplasia , dosing , bone marrow , pancytopenia , medicine , busulfan , aplasia , platelet , pure red cell aplasia , pharmacology , cyclophosphamide , chemotherapy
Summary 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.