MONOHYDROXYETHYLRUTOSIDE, A DOSE-DEPENDENT CARDIOPROTECTIVE AGENT, DOES NOT AFFECT THE ANTITUMOR-ACTIVITY OF DOXORUBICIN

The cumulative dose-related cardiotoxicity of doxorubicin is believed to be caused by the production of oxygen-free radicals, 7-Monohydroxye thylrutoside (monoHER), a semisynthetic flavonoid and powerful antioxi dant, was investigated with respect to the prevention of doxorubicin-i nduced cardiotoxicity in mice and to its influence on the antitumor ac tivity of doxorubicin irt vitro and in vivo, Nontumor-bearing mice wer e equipped with a telemeter in the peritoneal cavity, They were given six weekly doses of 4 mg/kg doxorubicin i.v,, alone or in combination with either 100 or 250 mg/kg monoHER i,p,, 1 h prior to doxorubicin ad ministration and for the following 4 days, Cardiotoxic effects were me asured from electrocardiogram changes up to 2 weeks after treatment, P rotection against cardiotoxicity was found to be dose dependent, with 53 and 75% protection, respectively, as calculated from the reduction in the increase in the ST interval, MonoHER and several other flavonoi ds with good antioxidant properties were tested for their antiprolifer ative effects in the absence or the presence of doxorubicin in A2780 a nd OVCAR-3 human ovarian cancer cells and MCF-7 human breast cancer ce lls ill vitro, Some flavonoids were directly toxic at 50 and 100 mu M, whereas others, including monoHER, did not influence the antiprolifer ative effects of doxorubicin at these concentrations, The influence of monoHER was further tested on the growth-inhibitory effect of 8 mg/kg doxorubicin i,v,, given twice with an interval of 1 week in A2780 and OVCAR-3 cells that were grown as s,c, xenografts in nude mice, MonoHE R, administered 1 h before doxorubicin in a dose schedule of 500 mg/kg i,p, 2 or 5 days per week, was not toxic and did not decrease the ant itumor activity of doxorubicin. It can be concluded that monoHER showe d a dose-dependent protection against chronic cardiotoxicity and did n ot influence the antitumor activity of doxorubicin in vitro or in vivo .