Advertisement

Metabolic Activation of Adriamycin by Nadph-Cytochrome P-450 Reductase, Rat Liver and Heart Microsomes and Covalent Protein Binding of Metabolites

  • Max E. Scheulen
  • Hermann Kappus
Part of the Advances in Experimental Medicine and Biology book series (AEMB)

Abstract

The anthracycline antibiotic adriamycin is a highly effective anticancer chemotherapeutic agent (Blum and Carter, 1974). Its clinical use is limited to a total dose of 550 mg/sq m body surface by cumulative cardiotoxicity (Lefrak et al., 1973). As there is no reliable in vitro-test system for the cardiotoxicity of new anthracyclines pathological and electrocardiographical evaluations in mouse, rat, and rabbit are mainly used (Zbinden and Brändle, 1975; Mettler et al., 1977).

Keywords

Covalent Binding Microsomal Protein Anthracycline Antibiotic Microsomal Electron Transport Adriamycin Cardiotoxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bachur, N., Gordon, S., and Gee, M., 1977, Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation, Mol.Pharmacol.,13:901-910.Google Scholar
  2. Bachur, N.R., Gordon, S.L., and Gee, M.V., 1978, A general mechanism for microsomal activation of quinone anticancer agents to free radicals, Cancer Res., 38: 1745–1750.Google Scholar
  3. Bachur, N.R., Gordon, S.L., Gee, M.V., and Kon, H., 1979, NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals, Proc.Natl.Acad.Sci.USA,76:954-957.Google Scholar
  4. Bertazzoli, C., Sala, L., Bllerini, L., Watanabe, T., and Folkers, K., 1976, Effect of adriamycin on the activity of the succinate dehydrogenase-coenzyme Q10 reductase of the rabbit myocardium, Res.Commun.Chem.Pathol.Pharm.,15:797 -800.Google Scholar
  5. Blum, R.H., and Carter, S.K., 1974, Adriamycin: A new anticancer drug with significant clinical activity, Ann.Intern.Med., 80: 249–259.PubMedCrossRefGoogle Scholar
  6. Bolt, H.M., and Kappus, H., 1974, Irreversible binding of ethynyl-estradiol metabolites to protein and nucleic acids as catalyzed by rat liver microsomes and mushroom tyrosinase, J.Steroid.Biochem.,5:179-184.Google Scholar
  7. Breed, J.G.S., Zimmermann, A.N.E., Dormans, J.A.M.A., and Pinedo, H.M., 1980, Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in the rabbit, Cancer stes., 40: 2033–2038.Google Scholar
  8. Burton, G.M.; Henderson, C.A., Balcerzak, S.P., and Sagone, Jr., A.L., 1979, Effect of adriamycin on the metabolism of heart slices, Int.J.Radiation Oncology Biol.Phys.,5:1287-1289.Google Scholar
  9. Byfield, J.E., 1977, Adriamycin cardiac toxicity: A different hypothesis, Cancer Treat.Rep., 61: 497–498.Google Scholar
  10. Doroshow, J.H., and Reeves, J., 1980, A. nthracycline-enhanced oxygen radical formation in the heart, Proc.Amer.Ass.Cancer Res. A.er.Soc.Clin.Oncol.,21:266, abstr. 1067.Google Scholar
  11. Goodman, J., and Hochstein, P., 1977, Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin, Biochem. Biophys.Res.Commun.,77:797–803.Google Scholar
  12. Handa, K., and Sato, S., 1975, Generation of free radicals of quinone group-containing anticancer chemicals in an NADPH-microsome system as evidenced by initiation of sulfite oxidation, Gann, 66: 43–47.PubMedGoogle Scholar
  13. Iwamoto, Y., Hansen, I.L., Porter, T.H., and Folkers, K., 1974, Inhibition of coenzyme Q10-enzymes, succinoxidase and NADH-oxi-dase by adriamycin and other quinones having antitumor activity, Biochem.Biophys.Res.Commun.,58:633–638.Google Scholar
  14. Kishi, T., Watanabe, T., and Folkers, K., 1976, Bioenergetics in clinical medicine: Prevention by forms of coenzyme Q of the inhibition by adriamycin of coenzyme Q10-enzymes in mitochondria of the myocardium, Proc.Natl.Acad.Sci.USA,73:4653–4656.Google Scholar
  15. Lefrak, E.A., Ptha, J. Rosenheim, S. and Gottlieb, J.A., 1973, A clinicopathologic analysis of adriamycin cardiotoxicity, Cancer, 32: 302–314.Google Scholar
  16. Locker, G.Y., Doroshow, J.H., and Myers, C.E., 1977, Glutathione peroxidase: Its role in adriamycin cardiotoxicity, Proc.Amer. Ass.Cancer Res. Amer.Soc.Clin.Oncol.,18:87, abstr. 348.Google Scholar
  17. Lown, J.W., Sim, S., Majumdar, K.C., and Chang, R.-Y., 1977, Strand scission of DNA by bound adriamycin and daunomycin in the presence of reducing agents, Biochem.Biophys.Res.Commun., 76: 705–710.PubMedCrossRefGoogle Scholar
  18. Lowry, 0.H., Rosenbrough, N.J., Farr, A.L., and Randall, R.J., 1951, Protein measurement with the Folin phenol reagent, J.Biol.Chem., 193: 265–275.Google Scholar
  19. Lucacchini, A., Martini, C., Segnini, D., and Ronca, G., 1979, Evidence of soluble protein binding adriamycin by affinity chromatography, Experientia,35:1148–1149.Google Scholar
  20. Mailer, K., and Petering, D.H., 1976, Inhibition of oxidative phosphorylation in tumor cells and mitochondria by daunomycin and adriamycin, Biochem.Pharmacol.,25:2085–2089.Google Scholar
  21. Marco, A., 1975, Adriamycin (NSC-123127): Mode and mechanism of action, Cancer Chemotherapy Rep. Pt.3, 6: 91–106.Google Scholar
  22. Mettler, FTP.,Young, D.M., and Ward, J.M., 1977, Adriamycin-induced cardiotoxicity (cardiopathy and congestive heart failure) in rats, Cancer Res.,37:2705–2713.Google Scholar
  23. Mimnaugh, E.G., Siddik, Z.H., Drew, R., Sikic, B.I., and Gram, T.E., 1979, The effects of alpha-tocopherol on the toxicity, disposition, and metabolism of adriamycin in mice, Toxicol. Appl.Pharmacol., 49: 119–126.CrossRefGoogle Scholar
  24. Momparler, R.L., Karon, M., Siegel, S.E., and Avila, F., 1976, Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free system and intact cells, Cancer Res., 36: 2891–2895.Google Scholar
  25. Olson, H.M., and Capen, C.C., 1978, Chonic cardiotoxicity of doxorubicin in the rat: Morphologic and biochemical investigations, Toxicol.Appl.Pharmacol.,44:605–616.Google Scholar
  26. Omura, T., and Takesue, S., 1970, A new method for simultaneous purification of cytochrome b5 and NADPH-cytochrome c reductase from rat liver microsomes, J.Biochem.(Tokyo),67:249–257.Google Scholar
  27. Reed, D.J., and Babson, J.R., 1980, Adriamycin-BCNU mediated plasma membrane leakage and loss of glutathione protection with normal and tumor cells, Proc.Amer.Ass.Cancer.Res. Amer.Soc. Clin.Oncol.,21:307, abstr. 1230.Google Scholar
  28. Remmer, H., Greim, H., Schenkman, J.B., and Estabrook, R.W., 1967, Methods for the elevation of hepatic microsomal mixed function oxidase levels and cytochrome P450, Meth.Enzymol.,10:703–708.Google Scholar
  29. Ross, W., 1980, Adriamycin-induced DNA double strand breaks, Proc. Amer.Ass.Cancer Res. Amer.SOc.Clin.Oncol.,21:274, abstr. 1100.Google Scholar
  30. van Rossum, G.D.V., and Gosâlvez, M., 1976, Inhibition of ion-transport by the antitumour antibiotic adriamycin, Fed.Proc., 35: 3, 3201.Google Scholar
  31. Schwartz, H.S., 1975, DNA breaks in P-288 tumor cells in mice after treatment with daunorubicin and adriamycin, Res.Commun. Chem. Path.Pharmacol.,10:51–64.Google Scholar
  32. Scheulen, M., Wollenberg, P., Bolt, H.M., Kappus, H., and Remmer, H., 1975, Irreversible binding of dopa and dopamine metabolites to protein by rat liver microsomes, Biochem.Biophys.Res.Commun., 66: 1396–1400.PubMedCrossRefGoogle Scholar
  33. Taylor, D., and Hochstein, P., 1978, Inhibition by adriamycin of a metmyoglobin reductase from beef heart, Biochem.Pharmacol., 27: 2079–2082.PubMedCrossRefGoogle Scholar
  34. Yamanaka, N., Kato, T., Nishida, K., Fujikawa, T., Fukushima, M., and Ota, K., 1979, Elevation of serum lipid peroxide level associated with doxorubicin toxicity and its amelioration by (dl)-alpha-tocopheryl acetate or coenzyme Q10 in mouse, Cancer Chemother.Pharmacol., 3:223–227’.Google Scholar
  35. Yasumi, M., Minaga, T., Takamura, K., Kizu, A., and Ijichi, H., 1980, Inhibition of cardiac NADP-linked isocitrate dehydrogenase by adriamycin, Biochem.Biophys.Res.Commun.,93:631–636.Google Scholar
  36. Zbinden, G., and Brändle, E., 1975, Toxicology screening of daunorubicin (NSC-82151), adriamycin (NSC-123127), and their derivatives in rats, Cancer Chemotherapy Rep., 59: 707–715.Google Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • Max E. Scheulen
    • 1
  • Hermann Kappus
    • 2
  1. 1.Innere Klinik und Poliklinik (Tumorforschung),Westdeutsches TumorzentrumUniversität EssenEssen 1Germany
  2. 2.Abteilung für PharmakologieMedizinisches Institut für UmwelthygieneUniversität DüsseldorfDüsseldorfGermany

Personalised recommendations