Lecithinized copper,zinc-superoxide dismutase as a protector against doxorubicin-induced cardiotoxicity in mice.
Production of superoxide radicals from doxorubicin is widely accepted to be the cause of the cardiotoxicity induced by this antitumor agent. Pretreatment with superoxide dismutase could improve the therapeutic application. Aim of the present study was to determine whether lecithinized superoxide dismutase (PC-SOD) can serve as a cardioprotective drug during doxorubicin treatment. The protective potential of PC-SOD on doxorubicin-induced cardiotoxicity was investigated in BALB/c mice. The possible influence of PC-SOD on the antitumor activity of doxorubicin was investigated in vitro as well as in vivo. Mice were treated intravenously with doxorubicin (4 mg x kg(-1)) or doxorubicin and PC-SOD (5000, 20000 or 80000 U x kg(-1)) weekly x 6 and appropriate controls were included. Cardiotoxicity was monitored for 8 weeks by ECG measurement. The influence of PC-SOD on the antitumor activity of doxorubicin was evaluated in three human malignant cell lines. Nude mice bearing OVCAR-3 human ovarian cancer xenografts were treated intravenously with doxorubicin (8 mg x kg(-1)) alone or preceded by PC-SOD 20000 or 80000 U x kg(-1) weekly x 2 and appropriate controls were included. PC-SOD prevented doxorubicin-induced cardiotoxicity already at 5000 U x kg(-1) whereas 20000 and 80000 U x kg(-1) were equally protective. No toxicity was observed in mice treated with PC-SOD. PC-SOD did not interfere with the antiproliferative effects of doxorubicin in vitro. In vivo, PC-SOD had no negative effect on the inhibition of xenograft growth induced by doxorubicin. It can be concluded that PC-SOD protects the heart, but not the tumor against doxorubicin. These data suggest that PC-SOD may be a suitable cardioprotector during doxorubicin treatment.
den Hartog
Gertjan J M
GJ
Department of Pharmacology and Toxicology, University Maastricht, 6200 MD Maastricht, The Netherlands. gj.denhartog@farmaco.unimaas.nl
Haenen
Guido R M M
GR
Boven
Epie
E
van der Vijgh
Wim J F
WJ
Bast
Aalt
A
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005260:Female; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000517:prevention & control; D010713:Phosphatidylcholines / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000494:pharmacology* / Q000627:therapeutic use
D006131:Growth Inhibitors; D010713:Phosphatidylcholines; D004317:Doxorubicin; D013482:Superoxide Dismutase; C434045:lecithinized superoxide dismutase