Timing of treatment with ICRF-187 and its effect on chronic doxorubicin cardiotoxicity

• Published in: Cancer chemotherapy and pharmacology 1993, Vol.32 (6), p.445-449
• Main Authors: HERMAN, E. H, FERRANS, V. J
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Body Weight - drug effects; Cardiomyopathies - chemically induced; Cardiomyopathies - prevention & control; Dogs; Doxorubicin - antagonists & inhibitors; Doxorubicin - toxicity; Drug toxicity and drugs side effects treatment; Female; Male; Medical sciences; Pharmacology. Drug treatments; Razoxane - pharmacology; Time Factors; Toxicity: cardiovascular system
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/BF00685888

Studies were conducted to evaluate whether the timing of administration of ICRF-187 [(+)-1,2-bis(3,5 dioxopiperazinyl-1-yl)propane] would influence the degree of cardioprotection provided by this agent against the development of doxorubicin-induced chronic cardiomyopathy. Beagle dogs (8.5-14 kg) received either doxorubicin alone (1.75 mg/kg, i.v., n = 8), doxorubicin (1.75 mg/kg) simultaneously with ICRF-187 (35 mg/kg, i.v., n = 8), or doxorubicin (1.75 mg/kg) followed 2 h later by ICRF-187 (35 mg/kg, n = 8). Control animals received ICRF-187 (35 mg/kg, n = 4) or saline (n = 4). All animals received a course of seven treatments, each given 3 weeks apart, and were killed 3 weeks after the last treatment. Semiquantitative grading of histologic sections of myocardium showed that as compared with animals treated with doxorubicin alone, the incidence and the severity of the doxorubicin-induced myocardial lesions were reduced in the two groups of animals given doxorubicin plus ICRF-187. However, protection was significantly better in dogs receiving ICRF-187 and doxorubicin simultaneously than in those given ICRF-187 2 h after doxorubicin. These observations were interpreted as indicating that the timing of administration of ICRF-187 with respect to that of doxorubicin is an important factor in determining the degree of cardioprotection and that there is a "time window" in which ICRF-187 exerts optimal effects.