The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro.
The anthrapyrazole CI941 is one of a new series of DNA complexing drugs which displays high level broad spectrum antitumour activity in mice. In view of the proposed role of drug free radical formation, superoxide generation and lipid peroxidation in anthracycline and anthraquinone induced toxicities, the redox biochemistry of CI941 has been investigated. Studies have been performed in vitro using rat liver microsomes and purified cytochrome P-450 reductase. In addition, the ability of CI941 to undergo chemical reduction has been examined. Pulse radiolysis of CI941 demonstrated that the drug can undergo chemical reduction with a one electron reduction potential of E1(7) = -538 +/- 10 mV. However, electron spin resonance (ESR) spectroscopy studies using either NADPH fortified microsomes or cytochrome P-450 reductase, failed to detect a drug free radical signal. Unlike doxorubicin, CI941 (150 microM) inhibited basal rate microsomal NADPH consumption by 45%. Furthermore, CI941 (50-200 microM) antagonised doxorubicin stimulated (1.8-fold) NADPH oxidation by over 50%. CI941 also antagonised the formation of a doxorubicin free radical ESR signal in a concentration dependent manner. CI941 induced minimal superoxide generation in the presence of either microsomes or cytochrome P-450 reductase and inhibited doxorubicin induced (50 microM) superoxide formation by up to 80% (50-200 microM CI941). Importantly, CI941 inhibits both basal rate and doxorubicin (100 microM) stimulated lipid peroxidation (52% inhibition at 5 microM CI941). These data suggest that CI941 is unlikely to induce free radical mediated tissue damage in vivo. On the contrary, CI941 may have a protective role if used in combination with doxorubicin.
Graham
M A
MA
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Newell
D R
DR
Butler
J
J
Hoey
B
B
Patterson
L H
LH
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000494:pharmacology*; D011675:Pulse Radiolysis; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D047069:Pyrazolones; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism*
D000880:Anthraquinones; D000970:Antineoplastic Agents; D005609:Free Radicals; D008054:Lipid Peroxides; D011720:Pyrazoles; D047069:Pyrazolones; D013481:Superoxides; C050637:losoxantrone; D009249:NADP; D004317:Doxorubicin; D009251:NADPH-Ferrihemoprotein Reductase