In vitro evidence of drug action in aplastic anemia

Vincent, Paul

doi:10.1007/bf00320378

Cited by 13 publications

(7 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Against this background of the aetiology of the human disease, there have been various attempts to produce experimental models of AA in small laboratory animals using infectious agents, radiation, drugs and chemicals, and antibodies (Alter et al . 1978; Haak 1980; Vincent 1984). Of these, probably the most useful model has proved to be that of Morley & Blake (1974) who developed a mouse model of chronic hypoplastic marrow failure (CHMF) (i.e.…”

Section: Discussionmentioning

confidence: 99%

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

Turton¹,

Andrews

Havard

et al. 2002

Int J Experimental Path

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Turton¹,

Andrews

Havard

et al. 2002

Int J Experimental Path

View full text Add to dashboard Cite

show abstract

“…Furthermore, although the development of animal models of chronic bone marrow hypoplasia/aplasia (i.e. AA) has been attempted, none has become reliably used in the elucidation of the pathogenesis of the human disease (Benestad 1979;Haak 1980;Appelbaum and Fefer, 1981;Vincent 1984Vincent , 1986FAO/WHO 1988, Young andMaciejewski 1997). Furthermore, no experimental animal models are currently used in preclinical toxicology studies carried out by the pharmaceutical industry to assess the potential of drugs in development to induce AA (see Young and Keisu 1996).…”

Section: Introductionmentioning

confidence: 99%

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

et al. 2010

View full text Add to dashboard Cite

Many anticancer drugs are myelotoxic and cause bone marrow depression; however, generally, the marrow/blood returns to normal after treatment. Nevertheless, after the administration of some anti-neoplastic agents (e.g. busulphan, BU) under conditions as yet undefined, the marrow may begin a return towards normal, but normality may not be achieved, and late-stage/residual marrow injury may be evident. The present studies were conducted to develop a short-term mouse model (a 'screen') to identify late-stage/residual marrow injury using a brief regimen of drug administration. Female BALB/c mice were treated with BU, doxorubicin (DOX), cisplatin (CISPLAT) or cyclophosphamide (CYCLOPHOS) on days 1, 3 and 5. In 'preliminary studies', a maximum tolerated dose (MTD) for each drug was determined for use in 'main studies'. In main studies, mice were treated with vehicle (control), low and high (the MTD) dose levels of each agent. Necropsies were performed, and blood parameters and femoral/humeral nucleated marrow cell counts (FNCC/HNCC) were assessed on six occasions (from days 1 to 60/61 post-dosing). Late-stage/residual changes were apparent in BU-treated mice at day 61 post-dosing: RBC, Hb and haematocrit were reduced, mean cell volume/mean cell haemoglobin were increased and platelet and FNCC counts were decreased. Mice given DOX, CISPLAT and CYCLOPHOS, in general, showed no clear late-stage/residual effects (day 60/61). It was concluded that a brief regimen of drug administration, at an MTD, with assessment at day 60/61 post-dosing was a suitable short-term method/screen in the mouse for detecting late-stage/residual marrow injury for BU, a drug shown to exhibit these effects in man.

show abstract

“…A variety of aetiological agents have been associated with AA, and in particular, radiation, chemicals and drugs, and viral infections (Freedman 2000;Heimpel 2000). Although the development of rodent models of chronic bone marrow hypoplasia/aplasia has been attempted, none has become widely used to elucidate the pathogenesis of the human disease (Alter et al 1978;Benested 1979;Haak 1980;Appelbaum & Fefer 1981;Vincent 1984Vincent , 1986FAO/WHO 1988;Young & Maciejewski 1997). Although the development of rodent models of chronic bone marrow hypoplasia/aplasia has been attempted, none has become widely used to elucidate the pathogenesis of the human disease (Alter et al 1978;Benested 1979;Haak 1980;Appelbaum & Fefer 1981;Vincent 1984Vincent , 1986FAO/WHO 1988;Young & Maciejewski 1997).…”

mentioning

confidence: 99%

“…Nevertheless, the basic pathophysiology of AA is not clearly understood, and a contributing factor to this is that there are no convenient animal models of the disease. Although the development of rodent models of chronic bone marrow hypoplasia/aplasia has been attempted, none has become widely used to elucidate the pathogenesis of the human disease (Alter et al 1978;Benested 1979;Haak 1980;Appelbaum & Fefer 1981;Vincent 1984Vincent , 1986FAO/WHO 1988;Young & Maciejewski 1997). Nevertheless, of the various investigations to develop rodent models of AA, useful results have been obtained in studies based on methods described by Morley & Blake (1974a).…”

mentioning

confidence: 99%

The haemotoxicity of mitomycin in a repeat dose study in the female CD‐1 mouse

Molyneux

Gibson

Gordon‐Smith

et al. 2005

Int J Experimental Path

View full text Add to dashboard Cite

Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose-related, bone marrow depression in man and laboratory animals; this change is generally reversible. However, there is evidence that MMC may also cause a late-stage or residual bone marrow injury. The present study in female CD-1 mice investigated the haematological and bone marrow changes induced by MMC in a repeat dose study lasting 50 days. Control and MMC-treated mice were dosed intraperitoneally on eight occasions over 18 days with vehicle, or MMC at 2.5 mg/kg, autopsied (n = 6-12) at 1, 7, 14, 28, 42 and 50 days after the final dose and haematological changes investigated. Femoral nucleated bone marrow cell counts and levels of apoptosis were also evaluated and clonogenic assays carried out; serum levels of FLT3 ligand (FL) were assessed. At day 1 post-dosing, MMC induced significant reductions in RBC, Hb and haematocrit (HCT) values, and there were decreases in reticulocyte, platelet, and femoral nucleated cell counts (FNCC); neutrophil, lymphocyte and monocyte values were also significantly reduced. On days 7 and 14 post-dosing, all haematological parameters showed evidence of a return towards normal values, but at these times, and at day 28, values for RBC and FNCC remained significantly reduced in comparison with controls. At days 42 and 50 post-dosing, many haematological parameters in MMC-treated mice had returned to control levels; however, there remained evidence of late-stage effects on RBC, Hb and HCT values, and FNCC also continued to be significantly decreased. Results for granulocyte-macrophage colony-forming units and erythroid colonies showed a profound decrease immediately post-dosing, but a return to normal values was evident at day 50. Serum FL concentrations demonstrated very significant increases in the immediate post-dosing period, but a return to normal was seen at day 50 post-dosing; a relatively similar pattern was seen in the number of apoptotic femoral marrow nucleated cells. The histopathological examination of kidney tissues from MMC animals at day 42 and 50 post-dosing showed evidence of hydronephrosis with cortical glomerular/tubular atrophy and degeneration. It is therefore concluded that MMC administered on eight occasions over 18 days to female CD-1 mice at 2.5 mg/kg induced profound changes in haematological and bone marrow parameters in the immediate post-dosing period with a return to normal levels at day 50 post-dosing; however, there was evidence of mild but significant late-stage/residual effects on RBC and FNCC, and on cells of the erythroid lineage in the bone marrow.

show abstract

In vitro evidence of drug action in aplastic anemia

Cited by 13 publications

References 57 publications

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

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

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

The haemotoxicity of mitomycin in a repeat dose study in the female CD‐1 mouse

Contact Info

Product

Resources

About