Cardiotoxicity of combined administration of adriamycin and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats-with special reference to 125I-MIBG cardioautoradiography and histopathological findings.
We studied whether adriamycin(ADM)-induced myocardial disorder in rats is advanced when recombinant human granulocyte colony-stimulating factor (rhG-CSF) is administered. Rats were divided into three groups (15 rats/group), i.e. the ADM group, the ADM+rhG-CSF group, and the vehicle-treated control group. ADM (2 mg/kg, i.p.) was administered for the first 2 days in each cycle and 10 days of administration of rhG-CSF (50 micrograms/kg, s.c.) was started two days after the second dose of ADM was given in each cycle. The dosing cycle was repeated 3 times. One day after the last dose, the following parameters were analyzed: peripheral blood and bone marrow cells, electrocardiogram (ECG) and histopathological findings. Four hours after intravenous administration of 125I-metaiodobenzylguanidine (125I-MIBG), accumulation of 125I-MIBG in some organs and findings from autoradiography (ARG) of the heart were examined. ECG revealed an extended ventricular activation (VAT) time in the ADM and ADM+rhG-CSF groups. In histopathological analysis, vacuolar degeneration of the myocardium was observed in both the ADM and ADM+rhG-CSF groups. The degree of change was the same for both groups. The accumulation of 125I-MIBG in the heart was lower in both the ADM and ADM+rhG-CSF groups than in the control group. The same tendency was observed in ARG, but the difference between the ADM group and the ADM+rhG-CSF group was not significant. These results suggest that administration of rhG-CSF at the standard clinical dose does not aggravate ADM-induced myocardial disorder. However, because this disorder may be more clearly manifested by treatment with higher doses of ADM, it is necessary to conduct further studies on the methods of dosing and administration.
First Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
N
N
Niitsu
J I
JI
Yamazaki
M
M
Sato
T
T
Misaizu
I
I
Serizawa
K
K
Amano
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001345:Autoradiography / Q000379:methods; D001772:Blood Cell Count / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced; D002624:Chemistry, Clinical; D004317:Doxorubicin / Q000008:administration & dosage; D004562:Electrocardiography; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects*; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D009206:Myocardium / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D010544:Peroxidases / Q000097:blood; D011875:Radionuclide Angiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage
D000903:Antibiotics, Antineoplastic; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D010544:Peroxidases