PROTECTIVE EFFECT OF BUTYLATED HYDROXYANISOLE ON ADRIAMYCIN-INDUCED CARDIOTOXICITY

Adriamycin has a wide spectrum of antitumour activity with dose-relate d cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen free radicals. The o bjective of the present study was to investigate the influence of the antioxidant, butylated hydroxyanisole co-therapy on the cardiotoxicity of adriamycin, in-vivo. The aqueous solubility of butylated hydroxyan isole was enhanced by inclusion complex formation with hydroxypropyl-b eta-cyclodextrin. The extent of drug-induced myocardial damage in rats was assessed using intravenous (111)-labelled antimyosin Fab and chro nological changes in serum creatine kinase levels. There was a dose-re lated increase in myocardial antimyosin uptake in rats, which reached a plateau at an adriamycin dose of 10 mg kg(-1). The antimyosin uptake at this dose (% dose g(-1)=0 . 1942+/-0 . 0150, n=8) was significantl y reduced by co-administration of butylated hydroxyanisole with adriam ycin (10 mg kg(-1) of each) to 0 . 1462+/-0 . 0116 (n = 5, P < 0 . 05) . Assessment of cardiotoxicity in the rats was also performed by measu ring serial changes in serum creatine kinase levels. Increasing doses of adriamycin caused an increase in serum creatine kinase levels with peak values obtained between 2 and 8 h after dosing. These values decr eased upon co-administration of butylated hydroxyanisole with adriamyc in at 10 mg kg(-1) each and 30 mg kg(-1), each by 29 and 41%, respecti vely. On the other hand, butylated hydroxyanisole did not inhibit the tumouricidal activity of adriamycin as investigated in-vitro using the NMU rat mammary adenocarcinoma cell-line. The significant reduction i n anthracycline cardiotoxicity by butylated hydroxyanisole coadministr ation may result from its scavenging action on adriamycin-mediated fre e-radical formation or its enhancement of activity of enzymes involved in the metabolism of adriamycin.