The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse.
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.
Molyneux
Gemma
G
Department of Haematology, St George's Hospital Medical School, London, UK.
Gibson
Frances M
FM
Gordon-Smith
Edward C
EC
Pilling
Andrew M
AM
Liu
Kai Chiu
KC
Rizzo
Sian
S
Sulsh
Susan
S
Turton
John A
JA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D002452:Cell Count; D004334:Drug Administration Schedule; D004906:Erythrocyte Count; D005260:Female; D005269:Femur; D006400:Hematocrit; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006454:Hemoglobins / Q000032:analysis; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D008815:Mice, Inbred Strains; D016685:Mitomycin / Q000008:administration & dosage* / Q000009:adverse effects
D000903:Antibiotics, Antineoplastic; D006454:Hemoglobins; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016685:Mitomycin