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The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes

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Abstract

The ability of the cardioprotective agent ICRF-187 (dexrazoxane), its one-ring open hydrolysis products, and its two-ring open hydrolysis product, ADR-925, to displace Fe3+ from its complex with doxorubicin, daunorubicin, epirubicin and idarubicin have been studied. At pH 7.4, ICRF-187 at a concentration of 100 μM ICRF-187 slowly but completely displaced Fe3+ from its anthracycline complexes with half-times ranging from 230 to 450 min. The one-ring open intermediate hydrolysis products were also shown to be chelating agents and were also able to displace quickly and completely Fe3+ from its anthracycline complexes with half-times ranging from 1.7 to 16.7 min. Molecular modeling of Fe3+ complexes with the one-ring open intermediates showed that these intermediates were likely acting as tetradentate ligands. Since these intermediates are such good chelating agents, they may also be pharmacologically active species in preventing oxygen-radical derived iron-based anthracycline-induced cardiotoxicity. Since these one-ring open intermediates are produced by hydrolysis from the parent ICRF-187 more quickly than is ADR-925, the formation of pharmacologically active species might be occurring more quickly than previously thought. The displacement of Fe3+ from its anthracycline complexes by the two-ring open hydrolysis product ADR-925 also took place quickly and completely with half-times ranging from 1 to 3 min.

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References

  1. J. L. Speyer, M. D. Green, E. Kramer, M. Rey, J. Sanger, C. Ward, N. Dubin, V. Ferrans, P. Stecy, A. Zeleniuch-Jacquotte, J. Wernz, F. Feit, W. Slater, R. Blum and F. Muggia,Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. New Engl. J. Med.319, 745–752 (1988).

    Google Scholar 

  2. J. L. Speyer, M. D. Green, A. Zeleniuch-Jacquotte, J. C. Wernz, M. Rey, J. Sanger, E. Kramer, V. Ferrans, H. Hochster, M. Meyers, R. H. Blum, F. Feit, M.Attubato, W. Burrows and F. M. Muggia,ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J. Clin. Oncol.10, 117–127 (1992).

    Google Scholar 

  3. J. Koning, P. Palmer, C. R. Franks, D. E. Mulder, J. L. Speyer, M. D. Green and K. Hellmann,Cardioxane-ICRF-187, towards anticancer drug specificity through selective toxicity reduction. Cancer Treat. Rev.18, 1–19 (1991).

    Google Scholar 

  4. E. H. Herman, V. J. Ferrans, C. E. Myers and J. F. Van Vleet,Comparison of the effectiveness of (±)-1,2-Bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and n-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles. Cancer Res.45, 276–281 (1985).

    Google Scholar 

  5. E. H. Herman and V. J. Ferrans,Pretreatment with ICRF-187 provides long lasting protection against chronic daunorubicin cardiotoxicity in rabbits. Cancer Chemother. Pharmacol.16, 102–106 (1986).

    Google Scholar 

  6. P. M. Alderton, J. Gross and M. D. Green,Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model. Cancer Res.52, 194–201 (1992).

    Google Scholar 

  7. E. H. Herman, A. El-Hage, Y. Fukada and V. J. Ferrans,ICRF-187 reduces bleomycin-induced pulmonary toxicity in mice. FASEB J.3, A275 (1989).

    Google Scholar 

  8. C. E. Myers, L. Gianni, C. B. Simone, R. Klecker and R. Greene,Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry21, 1707–1713 (1982).

    Google Scholar 

  9. E. J. F. Demant and P. K. Jensen,Destruction of phospholipids and respiratory-chain activity in pig-heart submitochondrial particles induced by an adriamycin-iron complex. Eur. J. Biochem.132, 551–556 (1983).

    Google Scholar 

  10. L. Gianni, B. J. Corden and C. E. Myers,The biochemical basis of anthracycline toxicity and anti-tumor activity. Rev. Biochem. Toxicol.5, 1–82 (1983).

    Google Scholar 

  11. J. M. C. Gutteridge,Lipid peroxidation and possible hydroxyl radical formation stimulated by the self-reduction of a doxorubicin-iron (III) complex. Biochem. Pharmacol.33, 1725–1728 (1984).

    Google Scholar 

  12. B. Halliwell and J. M. C. Gutteridge, Free Radicals in Biology and Medicine, pp. 489–492, Clarendon, Oxford 1989.

    Google Scholar 

  13. K. M. Dawson,Studies on the stability and cellular distribution of dioxopiperazines in cultured BHK-21S cells. Biochem. Pharmacol.24, 2249–2253 (1975).

    Google Scholar 

  14. B. B. Hasinoff,The interaction of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane), its hydrolysis product ICRF-198, and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents and Actions26, 378–385 (1989).

    Google Scholar 

  15. B. B. Hasinoff,The iron(III)-adriamycin induced inactivation of the respiratory chain enzyme NADH cytochrome c reductase. Biochem. J.265, 865–870 (1990).

    Google Scholar 

  16. G. F. Vile and C. C. Winterbourn,dl-N,N′-dicarboxamidomethyl-N,N′-dicarboxymethyl-1,2-diaminopropane (ICRF-198) and d-1,2-bis(3,5-dioxopiperazine-1-yl)propane (ICRF-187) inhibition of Fe 3+ reduction, lipid peroxidation, and CaATPase inactivation in heart microsomes exposed to adriamycin. Cancer Res.50, 2307–2310 (1990).

    Google Scholar 

  17. D. D. Von Hoff, M. W. Lazard, P. Basa, H. L. Davis, A. L. Von Hoff, M. Rozencweig and F. Muggia,Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med.91, 710–717 (1979).

    Google Scholar 

  18. D. D. Von Hoff, M. Rozencweig, M. Layard, M. Slavik and F. M. Muggia,Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am. J. Med.62, 200–210 (1977).

    Google Scholar 

  19. T. G. Burke, T. D. Lee, J. van-Balgooy and J. H. Doroshow,Characterization of the aqueous decomposition products of (+) 1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane (ICRF-187) by liquid chromatographic and mass spectral analysis. J. Pharm. Sci.80, 338–340 (1991).

    Google Scholar 

  20. B. B. Hasinoff,Pharmacodynamics of the hydrolysis-activation of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane)). J. Pharm. Sci. (in press).

  21. Z.-X. Huang, P. M. May, K. M. Quinlan, D. R. Williams and A. M. Creighton,Metal binding by pharmaceuticals. Part 2. Interactions of Ca(II), Cu(II), Fe(II), Mg(II), Mn(II) and Zn(II) with the intracellular hydrolysis products of the antitumor agent ICRF-159 and its inactive homologue ICRF-192. Agents and Actions12, 536–542 (1982).

    Google Scholar 

  22. B. B. Hasinoff, F. X. Reinders and V. Clark,The enzymatic hydrolysis-activation of the adriamycin cardioprotective agent (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane. Drug Metab. Dispos.19, 74–80 (1991).

    Google Scholar 

  23. P. M. May, G. K. Williams and D. R. Williams,Speciation studies of adriamycin, quelamycin, and their metal ion complexes. Inorg. Chim. Acta46, 221–228 (1980).

    Google Scholar 

  24. B. B. Hasinoff,The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane). Agents and Actions29, 374–381 (1990).

    Google Scholar 

  25. T. G. Burke, C. A. Pritos, A. C. Sartorelli and T. R. Tritton,The structural basis for anthracycline antibiotic stimulation of oxygen consumption by HL-60 cells and mitochondria. Cancer Biochem. Biophys.9, 245–255 (1987).

    Google Scholar 

  26. U. Burkert and N. L. Allinger, Molecular Mechanics. ACD Monograph 177, American Chemical Society, Washington 1982.

    Google Scholar 

  27. B. B. Hasinoff,Oxyradical production results from the Fe 3+-doxorubicin complex undergoing self-reduction by its α-ketol group. Biochem. Cell. Biol.68, 1331–1336 (1990).

    Google Scholar 

  28. B. B. Hasinoff,The hydrolysis-activation of the doxorubicin cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane). Drug Metab. Dispos.18, 344–349 (1990).

    Google Scholar 

  29. C. K. Prout, D. S. Sanderson and M. C. Couldwell,N,N′-methylethylenebis (N-methylcarbamylglycinato) copper(II) dihydrate and N,N′-ethylethylenebis(N-methylcarbamylglycinato)-copper(II) dihydrate. Cryst. Struct. Comm.8, 181–188 (1979).

    Google Scholar 

  30. M. D. Lind, M. J. Hamor, T. A. Hamor and J. L. Hoard,Stereochemistry of ethylenediaminetetraacetato complexes. II. The structure of crystalline Rb[Fe(OH 2)Y·H 2 O]. III. The structure of crystalline Li[Fe(OH 2)Y·2H 2O]. Inorg. Chem.3, 34–43 (1964).

    Google Scholar 

  31. A. Hempel, N. Camerman and A. Camerman,Stereochemistry of the antitumor agent 4,4′-(1,2-propanediyl)bis(4-piperazine-2,6-dione): Crystal and molecular structure of the racemate (ICRF-159) and a soluble enantiomer (ICRF-187). J. Am. Chem. Soc.105, 3453–3456 (1982).

    Google Scholar 

  32. K. B. Nolan, T. Murphy, R. D. Hermanns and H. Rahoo,Chelating agents as antitumour drugs: Formation of chelating agents from the antitumor pro-drug razoxane. Inorg. Chim. Acta168, 283–288 (1990).

    Google Scholar 

  33. N. N. Daeid, K. B. Nolan and L. P. Ryan,Copper(II) complexes of hydrolysis products of the anticancer bis(3,5-dioxopiperazin-1-yl) alkanes. Displacement of co-ordinated carboxylate ligands by deprotonated amide groups in basic solution. J. Chem. Soc. Dalton Trans. 2301–2304 (1991).

  34. M. M. Sobol, R. G. Amiet and M. D. Green,In vitro evidence for direct complexation of ADR-529/ICRF-187[(+)-1,2-bis-(3,5-dioxo-piperazin-1-yl) propane] onto an existing ferric-anthracycline complex. Mol. Pharmacol.41, 8–17 (1992).

    Google Scholar 

  35. B. B. Hasinoff and J. P. Davey,Adriamycin and its iron(III) and copper(II) complexes; glutathione-induced dissociation; cytochrome c oxidase inactivation and protection; binding to cardiolipin. Biochem. Pharmacol.37, 3663–3669 (1988).

    Google Scholar 

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  1. Faculty of Pharmacy, University of Manitoba, R3T 2N2, Winnipeg, Manitoba, Canada

    Joan L. Buss & Brian B. Hasinoff

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  1. Joan L. Buss
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Buss, J.L., Hasinoff, B.B. The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes. Agents and Actions 40, 86–95 (1993). https://doi.org/10.1007/BF01976756

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