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

• Published in: International journal of experimental pathology Vol. 86; no. 6; pp. 415 - 430
• Main Authors: Molyneux, Gemma, Gibson, Frances M., Gordon-Smith, Edward C., Pilling, Andrew M., Liu, Kai Chiu, Rizzo, Sian, Sulsh, Susan, Turton, John A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden, USA Blackwell Publishing Ltd/Inc 01.12.2005; Blackwell Science; Blackwell Science Inc
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - adverse effects; Apoptosis; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Cell Count; Drug Administration Schedule; Erythrocyte Count; Female; Femur; haemotoxicity; Hematocrit; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - pathology; Hemoglobins - analysis; Investigative techniques, diagnostic techniques (general aspects); Kidney - drug effects; Kidney - pathology; Medical sciences; Membrane Proteins - blood; Mice; Mice, Inbred Strains; mitomycin; Mitomycin - administration & dosage; Mitomycin - adverse effects; mouse; myelotoxicity; Original; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Vertebrata; Anatomic pathology; Mammalia; Mitomycin; Mouse; Animal; Rodentia; haemotoxicity; myelotoxicity; Female; Dose
• ISSN: 0959-9673; 1365-2613
• DOI: 10.1111/j.0959-9673.2005.00452.x

Summary 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.