Long-term haematological alterations in female B6C3F1 mice treated with busulphan

Havard

et al. 2002

Summary. In man, chloramphenicol (CAP), induces two major haemotoxic effects. First, a reversible, dose-related reticulocytopenia and anaemia developing during treatment. Second, a non-dose-related aplastic anaemia (AA), developing weeks after treatment, is often irreversible and fatal. In previous studies, we developed a mouse model of the reversible reticulocytopenia/ anaemia using CAP succinate (CAPS); attempts to induce AA in the mouse with CAPS were unsuccessful; in the rat, CAPS induced only minimal haemotoxicity. We therefore wished to investigate haematological changes caused by CAPS in a third rodent, particularly in relation to the induction of significant`late stage' bone marrow depression (AA). Female guinea pigs were gavaged with CAPS in three experiments. In a dose ranging study, CAPS (at 2500 and 3500 mg/kg) was administered daily for 9 days, and blood examined at 1 day post dosing. CAPS induced increased erythrocyte values (an apparent haemoconcentration effect), and reduced reticulocytes and femoral marrow nucleated cell counts (FNCC). In a second experiment, CAPS was given at 333, 666 and 1000 mg/kg (13 days); haematological changes were compared with results from the initial study, with evidence of dose-related effects. In a final experiment, CAPS was administered (825 mg/ kg, 16 days) and blood studied at 1, 12, 28 and 63 days post dosing. At day 1, erythrocyte values were decreased (NS), and reticulocytes and FNCC were reduced; the marrow was hypocellular with erythroid depletion. At 12 and 28 days, values returned towards the normal range. At 63 days, parameters were normal. Thus, CAPS (825 mg/kg for 16 days) induced changes comparable to the reversible bone marrow depression seen in man; but there was no evidence of`late stage' (i.e. at 63 days) marrow depression, as would be seen in a developing or overt marrow aplasia (AA). The guinea pig (like the mouse) is a model for the early events, but is not a good model for CAPinduced AA in man.

Section: Discussionmentioning

confidence: 76%

Studies on the haemotoxicity of chloramphenicol succinate in the Dunkin Hartley guinea pig

Turton¹,

Havard

et al. 2002

“…In this model, BU was administered on four occasions, at 14 day intervals, over a six week period, at 20, 20, 20 and 10 mg/kg, respectively, to female Swiss or BALB/c mice, and the animals were studied over the following 300-400 days. We have investigated these findings (Andrews et al 1993(Andrews et al , 1997(Andrews et al , 1998, but used the female B6C3F 1 mouse, and gave four fortnightly doses of BU at dose levels from 10 to 40 mg/kg. However, in our experiments, lasting up to 497 days, we have been unable to obtain results which closely parallel those of Morley.…”

Section: Introductionmentioning

confidence: 99%

A new model of busulphan‐induced chronic bone marrow aplasia in the female BALB/c mouse

Gibson

Diamanti

et al. 2003

Summary. Aplastic anaemia (AA) is characterized by hypocellular marrow, pancytopenia, and risk of severe anaemia, haemorrhage and infection. AA is often idiopathic, but frequently occurs after exposure to drugs/chemicals. However, the pathogenesis of AA is not clearly understood, and there are no convenient animal models of drug-induced AA. We have evaluated regimens of busulphan (BU) administration in the mouse to produce a model of chronic bone marrow aplasia showing features of human AA. Mice were given 8 doses of BU at 0, 5.25 and 10.50 mg/kg over 23 days; marrow and blood samples were examined at 1, 19, 49, 91 and 112 days after dosing. At day 1 post dosing, in mice treated at 10.50 mg/kg, nucleated marrow cells, CFU-GM and Erythroid-CFU were reduced. Similarly, peripheral blood erythrocytes, leucocytes, platelets and reticulocytes were reduced. At day 19 and 49 post dosing, there was a trend for parameters to return towards normal. However, at day 91 and 112 post dosing, values remained significantly depressed, with a stabilized chronic bone marrow aplasia. At day 91 and 112 post dosing, marrow cell counts, CFU-GM and Erythroid-CFU were decreased; marrow nucleated cell apoptosis and c-kit + cell apoptosis were increased; peripheral blood erythrocyte, leucocyte, and platelet counts were reduced. We conclude that this is a model of chronic bone marrow aplasia which has many interesting features of AA. The model is convenient to use and has potential in several areas, particularly for investigations on mechanisms of AA pathogenesis in man.

“…over a 6‐week period) at 20, 20, 20 and 10 mg/kg; the animals were then studied over the following 300–400 days. We have investigated these reports (Andrews et al . 1993, 1997, 1998; Andrews 2000) using modifications of the original protocols but have been unable to obtain results which compare closely with those of Morley and Blake (1974a).…”

mentioning

confidence: 99%

“…over a 6-week period) at 20, 20, 20 and 10 mg/kg; the animals were then studied over the following 300-400 days. We have investigated these reports (Andrews et al 1993(Andrews et al , 1997(Andrews et al , 1998Andrews 2000) using modifications of the original protocols but have been unable to obtain results which compare closely with those of Morley and Blake (1974a). Accordingly, various regimens of BU dosing were re-examined in an attempt to produce an easily used mouse model of drug-induced AA, showing features of the human condition, and which developed within a relatively short period (about 120 days).…”

mentioning

confidence: 99%

Further development of a model of chronic bone marrow aplasia in the busulphan‐treated mouse

Turton

Sones

et al. 2006

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 5 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 5 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 5 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