title: The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat.
abstract: The protective activity of the bisdioxopiperazine ICRF-187 against the cardiotoxicity of doxorubicin was evaluated in the rat using both functional and histological assays. Animals that had received a single i.v. dose of doxorubicin (4 mg/kg) alone were compared with those that had been pretreated with a single i.v. injection of saline or ICRF-187 (40 or 60 mg/kg). All rats showed a transient reduction in body weight during the first 3 weeks after drug administration. The greatest reduction (approximately 16%) was observed in animals that had received a combination of ICRF-187 (40 or 60 mg/kg) and doxorubicin. Deaths related to cardiotoxicity were observed only in rats that had received doxorubicin alone and in those treated with saline; most of the deaths occurred at between 8 and 13 weeks after drug administration. Sequential assessments of heart function showed a persistent depression of cardiac output in animals that had received doxorubicin, with or without pretreatment with ICRF-187. The reduction in cardiac output observed in rats that had been pretreated with ICRF-187 (40 or 60 mg/kg) amounted to approximately 15% and approximately 30% after 12 and 20 weeks, respectively, indicating that cardioprotection was only partial. Nevertheless, this represented a marked improvement as compared with the approximately 35% reduction in cardiac output measured at 12 weeks in animals that had received doxorubicin but without pretreatment with ICRF-187. Histological examination of animals that had died during the course of the study and had received doxorubicin after pretreatment with saline revealed severe myocardial lesions typical of doxorubicin-induced damage. In contrast, animals that had been pretreated with ICRF-187 and survived for up to 20 weeks after treatment showed a marked amelioration of these lesions. The present findings may be interpreted as a true cardioprotection or a delay in the onset of the cardiotoxicity of doxorubicin resulting from pretreatment with the bisdioxopiperazine ICRF-187. Although prior and ongoing clinical trials clearly indicate that ICRF-187 protects patients well against doxorubicin-induced heart damage, further investigations are required before high doses of ICRF-187 can be used as a means of increasing the protective activity of this drug against doxorubicin-induced cardiotoxicity.
authors.affiliation: CRC Normal Tissue Radiobiology Research Group, (University of Oxford), Churchill Hospital, U.K.
authors.forename: T K
authors.initials: TK
authors.lastname: Yeung
authors.forename: R S
authors.initials: RS
authors.lastname: Jaenke
authors.forename: D
authors.initials: D
authors.lastname: Wilding
authors.forename: A M
authors.initials: AM
authors.lastname: Creighton
authors.forename: J W
authors.initials: JW
authors.lastname: Hopewell
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006333:Heart Failure / Q000139:chemically induced / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D010996:Pleural Effusion / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains; D011929:Razoxane / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D011929:Razoxane; D004317:Doxorubicin