Studies on the haemotoxicity of antineoplastic agents

Aplastic anaemia (AA) is a life-threatening disorder characterised by hypoplastic bone marrow and peripheral blood pancytopenia. The causes of AA are varied and include viruses, irradiation, chemicals and drugs. Recently, a new model of chronic bone marrow aplasia (CBMA) in the busulphan- (BU-) treated mouse was reported. In this model, female BALB/c mice treated with BU developed 'late-stage' (residual) CBMA on day 91 and 112 post dosing. In the mouse, CBMA shared many similarities with AA in man, however, treating mice with BU at a dose level of 10.50 mg/kg lead to high mortality. In subsequent studies, it was demonstrated that by lowering the dose of BU to 9.0 mg/kg, treated mice developed CBMA but without high levels of mortality. Initially, in the present investigations, the model of BU-induced CBMA in the mouse was used to measure changes in the concentration of the serum cytokine fms-like tyrosine kinase 3 (FLT3) ligand (FL). During periods of bone marrow aplasia the concentration of serum FL was increased. This elevation of FL was also inversely proportional to several peripheral blood and bone marrow parameters. The effects of administering the immunosuppressant drug cyclosporin A (CsA) to mice with BU-induce CBMA was assessed. When administered on day 57 post dosing for 30 days at 35 mg/kg/day, CsA did not protect mice from BU-induced CBMA. Experiments were also carried out using chlorambucil (CHB), mitomycin C (MMC) and azathioprine (AZA) to investigate if these drugs were capable of inducing significant bone marrow injury and late-stage (residual) effects. It was shown that CHB, MMC and AZA caused significant bone marrow depression in the immediate post dosing period, but did not cause significant late-stage (residual) bone marrow injury and CBMA. However, a mild residual effect on the erythroid lineage was evident in mice treated with MMC and with AZA. It is concluded that BU-induced CBMA in the mouse is a useful model for the study of the pathophysiological aspects of drug-induced bone marrow injury, and for the assessment of therapeutic agents employed to treat such conditions. Investigations on the haemotoxicity of CHB, MMC and AZA suggested that these agents were not suitable replacements for BU in the induction of CBMA