Doxorubicin-induced apoptosis in spontaneously hypertensive rats: differential effects in heart, kidney and intestine, and inhibition by ICRF-187.
The occurrence of apoptosis in heart, kidney and small intestine was investigated in spontaneously hypertensive rats (SHR) treated with doxorubicin (1 mg/kg/week for 6, 9 and 12 weeks) with and without pretreatment with the iron chelator ICRF-187 [(+)1.2-bis(3.5-dioxopiperazinyl-l-yl)propane] (25 mg/kg, i.p., given 30 min before doxorubicin). Animals receiving either ICRF-187 alone or saline were used as controls. Cells undergoing apoptosis were identified ultrastructurally and by staining using the nick-end labeling method. The results obtained by counting cells with positive nick-end labeling showed that, when given in cumulative doses of 9 and 12 (but not 6) mg/kg, doxorubicin induced significant toxicity in the heart, kidneys and intestine in association with apoptosis in epithelial cells of the intestinal mucosa and renal tubules but not in cardiac myocytes. At these doses nick end labeling in the heart was confined to occasional endothelial cells, interstitial dendritic cells and macrophages. The frequency of doxorubicin-induced apoptosis in renal and intestinal epithelial cells was decreased by pretreatment of the SHR with ICRF-187. Our data support the concept that the chronic cardiomyopathy induced by doxorubicin is not mediated by apoptosis of the cardiac myocytes.
Division of Research and Testing, Food and Drug Administration, Laurel, Maryland 20708, USA.
J
J
Zhang
J R
JR
Clark
E H
EH
Herman
V J
VJ
Ferrans
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000473:pathology*; D007150:Immunohistochemistry; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000494:pharmacology*
D002317:Cardiovascular Agents; D007502:Iron Chelating Agents; D011929:Razoxane; D004317:Doxorubicin