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. 1995 Apr;71(4):836–839. doi: 10.1038/bjc.1995.161

Indoloquinone EO9: DNA interstrand cross-linking upon reduction by DT-diaphorase or xanthine oxidase.

M Maliepaard 1, A Wolfs 1, S E Groot 1, N J de Mol 1, L H Janssen 1
PMCID: PMC2033736  PMID: 7536024

Abstract

We report DNA interstrand cross-linking caused by the anti-tumour indoloquinone EO9 following reductive activation with purified rat liver DT-diaphorase or xanthine oxidase. Reduction was a necessary event for cross-linking to occur. DNA cross-link formation by EO9 following DT-diaphorase reduction was completely inhibited by addition 10 microM dicoumarol, whereas only a minor effect of dicoumarol on xanthine oxidase-mediated DNA cross-linking by EO9 was observed. DNA cross-linking was pH dependent, with increasing cross-link formation from pH 5.5 to 7.0 for both DT-diaphorase and xanthine oxidase mediated reactions. Also, conversion of EO9 upon reduction was pH dependent. However, in contrast to DNA cross-linking, conversion rates of EO9 decreased at higher pH. EO9 was shown to be more efficient in DNA cross-linking than mitomycin C under identical conditions, using both DT-diaphorase and xanthine oxidase reductive activation at pH 5.5 and 7.0. This study indicates that the anti-tumour activity of EO9 may be at least partly mediated by interstrand DNA cross-link formation, and that various reducing enzymes may be important for activation of EO9 in vitro and in vivo.

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Selected References

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  1. Bailey S. M., Suggett N., Walton M. I., Workman P. Structure-activity relationships for DT-diaphorase reduction of hypoxic cell directed agents: indoloquinones and diaziridinyl benzoquinones. Int J Radiat Oncol Biol Phys. 1992;22(4):649–653. doi: 10.1016/0360-3016(92)90496-5. [DOI] [PubMed] [Google Scholar]
  2. Cresteil T., Jaiswal A. K. High levels of expression of the NAD(P)H:quinone oxidoreductase (NQO1) gene in tumor cells compared to normal cells of the same origin. Biochem Pharmacol. 1991 Aug 8;42(5):1021–1027. doi: 10.1016/0006-2952(91)90284-c. [DOI] [PubMed] [Google Scholar]
  3. Gustafson D. L., Pritsos C. A. Enhancement of xanthine dehydrogenase mediated mitomycin C metabolism by dicumarol. Cancer Res. 1992 Dec 15;52(24):6936–6939. [PubMed] [Google Scholar]
  4. Hendriks H. R., Pizao P. E., Berger D. P., Kooistra K. L., Bibby M. C., Boven E., Dreef-van der Meulen H. C., Henrar R. E., Fiebig H. H., Double J. A. EO9: a novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models. Eur J Cancer. 1993;29A(6):897–906. doi: 10.1016/s0959-8049(05)80434-4. [DOI] [PubMed] [Google Scholar]
  5. Lusthof K. J., Richter W., de Mol N. J., Janssen L. H., Verboom W., Reinhoudt D. N. Reductive activation of potential antitumor bis(aziridinyl)benzoquinones by xanthine oxidase: competition between oxygen reduction and quinone reduction. Arch Biochem Biophys. 1990 Feb 15;277(1):137–142. doi: 10.1016/0003-9861(90)90561-c. [DOI] [PubMed] [Google Scholar]
  6. Maliepaard M., de Mol N. J., Janssen L. H., Hoogvliet J. C., van der Neut W., Verboom W., Reinhoudt D. N. Reductive activation of potential antitumor mitosene compounds. J Med Chem. 1993 Jul 23;36(15):2091–2097. doi: 10.1021/jm00067a006. [DOI] [PubMed] [Google Scholar]
  7. Nakamura M., Yamazaki I. One-electron transfer reactions in biochemical systems. VII. Two types of electron outlets in milk xanthine oxidase. Biochim Biophys Acta. 1973 Dec 19;327(2):247–256. doi: 10.1016/0005-2744(73)90407-5. [DOI] [PubMed] [Google Scholar]
  8. Nemeikaite A., Cenas N. The changes of prooxidant and antioxidant enzyme activities in bovine leukemia virus-transformed cells. Their influence on quinone cytotoxicity. FEBS Lett. 1993 Jul 12;326(1-3):65–68. doi: 10.1016/0014-5793(93)81762-o. [DOI] [PubMed] [Google Scholar]
  9. Pan S. S., Andrews P. A., Glover C. J., Bachur N. R. Reductive activation of mitomycin C and mitomycin C metabolites catalyzed by NADPH-cytochrome P-450 reductase and xanthine oxidase. J Biol Chem. 1984 Jan 25;259(2):959–966. [PubMed] [Google Scholar]
  10. Phillips R. M., Hulbert P. B., Bibby M. C., Sleigh N. R., Double J. A. In vitro activity of the novel indoloquinone EO-9 and the influence of pH on cytotoxicity. Br J Cancer. 1992 Mar;65(3):359–364. doi: 10.1038/bjc.1992.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Robertson N., Stratford I. J., Houlbrook S., Carmichael J., Adams G. E. The sensitivity of human tumour cells to quinone bioreductive drugs: what role for DT-diaphorase? Biochem Pharmacol. 1992 Aug 4;44(3):409–412. doi: 10.1016/0006-2952(92)90429-m. [DOI] [PubMed] [Google Scholar]
  12. Ross D., Siegel D., Beall H., Prakash A. S., Mulcahy R. T., Gibson N. W. DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C. Cancer Metastasis Rev. 1993 Jun;12(2):83–101. doi: 10.1007/BF00689803. [DOI] [PubMed] [Google Scholar]
  13. Sharkis D. H., Swenson R. P. Purification by cibacron blue F3GA dye affinity chromatography and comparison of NAD(P)H:quinone reductase (E.C.1.6.99.2) from rat liver cytosol and microsomes. Biochem Biophys Res Commun. 1989 Jun 15;161(2):434–441. doi: 10.1016/0006-291x(89)92617-x. [DOI] [PubMed] [Google Scholar]
  14. Siegel D., Beall H., Senekowitsch C., Kasai M., Arai H., Gibson N. W., Ross D. Bioreductive activation of mitomycin C by DT-diaphorase. Biochemistry. 1992 Sep 1;31(34):7879–7885. doi: 10.1021/bi00149a019. [DOI] [PubMed] [Google Scholar]
  15. Walton M. I., Bibby M. C., Double J. A., Plumb J. A., Workman P. DT-diaphorase activity correlates with sensitivity to the indoloquinone EO9 in mouse and human colon carcinomas. Eur J Cancer. 1992;28A(10):1597–1600. doi: 10.1016/0959-8049(92)90049-8. [DOI] [PubMed] [Google Scholar]
  16. Walton M. I., Smith P. J., Workman P. The role of NAD(P)H: quinone reductase (EC 1.6.99.2, DT-diaphorase) in the reductive bioactivation of the novel indoloquinone antitumor agent EO9. Cancer Commun. 1991 Jul;3(7):199–206. doi: 10.3727/095535491820873164. [DOI] [PubMed] [Google Scholar]
  17. Workman P. Bioreductive mechanisms. Int J Radiat Oncol Biol Phys. 1992;22(4):631–637. doi: 10.1016/0360-3016(92)90493-2. [DOI] [PubMed] [Google Scholar]

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