The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse
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 i...
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| Published in | International journal of experimental pathology Vol. 86; no. 6; pp. 415 - 430 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford, UK; Malden, USA
Blackwell Publishing Ltd/Inc
01.12.2005
Blackwell Science Blackwell Science Inc |
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| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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. 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. |
| Author | Liu, Kai Chiu Pilling, Andrew M. Gordon-Smith, Edward C. Molyneux, Gemma Turton, John A. Sulsh, Susan Gibson, Frances M. Rizzo, Sian |
| Author_xml | – sequence: 1 givenname: Gemma surname: Molyneux fullname: Molyneux, Gemma organization: Department of Haematology, St George's Hospital Medical School, London, UK – sequence: 2 givenname: Frances M. surname: Gibson fullname: Gibson, Frances M. organization: Department of Haematology, St George's Hospital Medical School, London, UK – sequence: 3 givenname: Edward C. surname: Gordon-Smith fullname: Gordon-Smith, Edward C. organization: Department of Haematology, St George's Hospital Medical School, London, UK – sequence: 4 givenname: Andrew M. surname: Pilling fullname: Pilling, Andrew M. organization: Pathology Department, Huntingdon Life Sciences, Alconbury, Huntingdon, Cambridgeshire, UK, and – sequence: 5 givenname: Kai Chiu surname: Liu fullname: Liu, Kai Chiu organization: Pathology Department, Huntingdon Life Sciences, Alconbury, Huntingdon, Cambridgeshire, UK, and – sequence: 6 givenname: Sian surname: Rizzo fullname: Rizzo, Sian organization: Department of Haematology, St George's Hospital Medical School, London, UK – sequence: 7 givenname: Susan surname: Sulsh fullname: Sulsh, Susan organization: BIBRA International, Carshalton, Surrey, UK – sequence: 8 givenname: John A. surname: Turton fullname: Turton, John A. email: john.turton@ulsop.ac.uk organization: Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, London, UK |
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| Keywords | Vertebrata Anatomic pathology Mammalia Mitomycin Mouse Animal Rodentia haemotoxicity myelotoxicity Female Dose |
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| Notes | ark:/67375/WNG-9DX4L77J-6 ArticleID:IEP452 istex:D25204D005898BCBB3D53D55270CA04FC39B5D9B Present address: Prostate Stem Cell Laboratory, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. Present address: Microscience, Winnersh Triangle, Wokingham, Berkshire RG41 5TU, UK. |
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Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose‐related, bone marrow depression in man and laboratory animals; this change... Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose-related, bone marrow depression in man and laboratory animals; this change is... |
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| SubjectTerms | 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 |
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| Title | The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse |
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