Effects of ICRF-186 [(L)1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] on the toxicity of doxorubicin in spontaneously hypertensive rats.
An evaluation was made of the protective effects of ICRF-186 [(L)1,2-bis(3,5-dioxopiperazinyl-l-yl)propane], the L-enantiomer of ICRF-187 [(D)1,2-bis(3,5-dioxopiperazinyl-l-yl)propane], against the cardiotoxicity and nephrotoxicity induced in spontaneously hypertensive rats (SHR) by doxorubicin. SHR were given doxorubicin (1 mg/kg, i.v.), once a week for 12 weeks. Group 1 (n = 10) received doxorubicin alone; Groups 2, 3 and 4 (each, n = 5) received ICRF-186, 25 mg/kg (group 2), 12.5 mg/kg (group 3) or 6.25 mg/kg (group 4), i.p., 30 min before each dose of doxorubicin. Two groups of control animals (each, n = 5) received 12 weekly i.p. injections of saline or 25 mg/kg ICRF-186. ICRF-186 provided significant protection, in a dose-dependent manner, against the cardiotoxicity and nephrotoxicity of doxorubicin and attenuated the increases in cardiac immune effector cells (interstitial dendritic cells, cytotoxic T-helper lymphocytes and macrophages) associated with this cardiotoxicity. The results of the study were compared with those obtained with ICRF-187 under identical experimental conditions. Analysis of the cardiomyopathy scores, nephropathy scores and counts of the numbers of immune effector cells in the heart showed that, at a dose of 25 mg/kg, ICRF-186 is a somewhat less effective protectant than ICRF-187. At a dose of 12.5 mg/kg, both compounds induced generally similar degrees of protection. At a dose of 6.25 mg/kg, both had comparable, but only minimal, protective effects.
Zhang
J
J
Division of Research and Testing, Food and Drug Administration, Laurel, MD 20708.
Herman
E H
EH
Ferrans
V J
VJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002452:Cell Count / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006321:Heart / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000494:pharmacology*
D011929:Razoxane; D004317:Doxorubicin