Induction of Futile DNA Repair Processes by Bifunctional Intercalators

  • Bernard Lambert
  • Evelyne Segal-Bendirdjian
  • Bernard P. Roques
  • Jean-Bernard Le Pecq
Part of the NATO ASI Series book series (NSSA, volume 182)


Ditercalinium is a DNA bifunctional intercalator endowed with antitumor properties. It binds to DNA with high affinity, forming a noncovalent and reversible complex. NMR studies of a ditercalinium oligonucleotide complex have revealed that, in the DNA complex, the linking chain of ditercalinium is located in the large groove of the DNA double helix, and that a bending of the double helix is induced toward the small groove.

It was found that ditercalinium and its antitumor analogues, but not its monomeric derivative, elicit a specific toxicity on polA strains of E. coli. This toxicity is suppressed by the uvrA mutation. In polA strains, ditercalinium induces SOS functions, although no immediate DNA synthesis arrest is observed. In the thermosensitive ligase deficient strain lig7, single-strand breaks accumulate at non-permissive temperature. It is proposed that the structural alteration induced in DNA after ditercalinium binding is recognized by the UVR repair process in E. coli. Because of the noncovalent nature of the DNA-ditercalinium complex, this structural alteration acts as a mock lesion or a lure which triggers a futile and abortive repair process.

In mammalian cells, ditercalinium causes a delayed cytotoxicity. Cells treated with ditercalinium die only 5 to 6 generations after drug exposure. Mitochondrial DNA is rapidly lost, and no damage is observed on nuclear DNA. It is hypothesized that the loss of mitochondrial DNA is related to a malfunctioning of a DNA repair process. DNA structural alterations, caused by agents forming non-covalent and reversible complexes with DNA, appear as a new type of lesion which could, in some conditions, completely fool the DNA repair machinery, and which would then become deleterious for the cells.


Nonpermissive Temperature Covalent Adduct polA Strain Reversible Complex Small Groove 
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  1. Bendirdjian, J.-P., Delaporte, C., Roques, B. P., and Jacquemin-Sablon, A., 1984, Effects of 7H-pyridocarba-zole mono and bifunctional DNA-intercalators on Chinese hamster lung cells in vitro, Biochem. Pharmacol., 33: 3681.PubMedCrossRefGoogle Scholar
  2. Caron, P. R., Kushner, S. R., and Grossman, L., 1985, Involvement of helicase II (UvrD gene product) and DNA polymerase I in excision mediated by the uvrABC protein complex, Proc. Natl. Acad. Sci. USA, 82:4925.PubMedCrossRefGoogle Scholar
  3. Clayton, D. A., Doda, J. N., and Friedberg, E. C., 1974, The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria, Proc. Natl. Acad. Sci. USA, 71:2777.PubMedCrossRefGoogle Scholar
  4. Cummings, O. W., King, T. C., Holden, J. A., and Low, R. L., 1987, Purification and characterization of the potent endonuclease in extracts of bovine heart mitochondria, J. Biol. Chem., 262:2005.PubMedGoogle Scholar
  5. Delbarre, A., Delepierre, M., Garbay, C., Igolen, J., Le Pecq, J.-B., and Roques, B. P., 1987, Geometry of the antitumor drug Ditercalinium bisintercalated into d(CpGpCpG)2 by 1H NMR, Proc. Natl. Acad. Sci. USA. 84:2155.PubMedCrossRefGoogle Scholar
  6. Esnault, C., Roques, B. P., Jacquemin-Sablon, A., and Le Pecq, J.-B., 1984, Effectg of new antitumor bifunctional intercalators derived from 7H-pyridocarbazole on sensitive and resistant L1210 cells, Cancer Res., 44:4335.Google Scholar
  7. Fellous, R., Coulaud, D., El Abed, I., Roques, B. P., Le Pecq, J.-B., Delain, E., and Gouyette, A., 1988, In vivo and in vitro cytoplasmic accumulation of Ditercalinium in rat hepatocytes induces mitochondrial damages, Cancer Res. In press.Google Scholar
  8. Garbay-Jaureguiberry, C., Laugaâ, P., Delepierre, M., Laalami, S., Muzard, G., Le Pecq, J.-B., and Roques, B. P., 1987, DNA bis-intercalators as new antitumor agents: modulation of the anti-tumour activity by the linking chain rigidity in the Ditercalinium series, Anti-Cancer Drug Design, 1:323.PubMedGoogle Scholar
  9. Grossman, L., Caron, P. R., Mazur, S. J., and Oh, E. Y., 1988, Repair of DNA-containing pyrimidine dimers, FASEB J., 2:2696.PubMedGoogle Scholar
  10. Husain, I., Van Houten, B., Thomas, D. C., Abdel-Monem, M., and Sancar, A., 1985, Effect of DNA polymerase I and DNA helicase II on the turnover rate of UvrABC excision nuclease, Proc. Natl. Acad. Sci. USA, 82:6774.PubMedCrossRefGoogle Scholar
  11. Kanner, L., and Hanawalt, P. C., 1970, Repair deficiency in DNA polymerase, Biochem. Biophys. Res. Commun., 39:149.PubMedCrossRefGoogle Scholar
  12. Lambert, B., and Le Pecq, J.-B., 1982, Isolement et caract-érisation de souches d’ E. coli sensibles à des toxiques hydrophiles et/ou charges, C. R. Hebd. Seances, Acad. Sci., Ser. C., 294:447.Google Scholar
  13. Lambert, B., Roques, B. P., and Le Pecq, J.-B., 1988, Induction of an abortive and futile DNA repair process in E. coli by the antitumor DNA bifunctional inter-calator, Ditercalinium: role of polA in death induction, Nucleic Acids Res., 16:1063.PubMedCrossRefGoogle Scholar
  14. Laugâa, Ph., Markovits, J., Delbarre, A., Le Pecq, J.-B., and Roques, B. P., 1985, DNA tris-intercalation: First acridine trimer with DNA affinity in the range of DNA regulatory proteins. Kinetic studies. Biochemistry, 24:5567.Google Scholar
  15. Le Pecq, J.-B., and Roques, B.P., 1986, DNA binding and biological properties of bis-and trisintercalating molecules, in: ‘Mechanisms of DNA damage and repair, M. G. Simic, L. Grossman, and A. C. Upton, ed., Plenum Press Publ., New York, p. 219.CrossRefGoogle Scholar
  16. Markovits, J., Pommier, Y., Mattern, M. R., Roques, B. P., Le Pecq, J.-B., and Kohn, K. W., 1986, Effect of the bifunctional antitumor intercalator Ditercalinium on DNA in mouse leukemia (L1210) cells and on L1210 DNA topo isomerase II, Cancer Res., 46:5821.PubMedGoogle Scholar
  17. Meunier-Rotival, M., Soriano, P., Cuny, G., Strauss, F., and Bernadi, G., 1982, Sequence organisation and genomic distribution of the major family of interspersed repeats of mouse DNA, Proc. Natl. Acad. Sci. USA, 79:355.PubMedCrossRefGoogle Scholar
  18. Mita, S., Monnat, R. J., and Loeb, L. A., 1988, Resistance of HeLa cell mitochondrial DNA to mutagenesis by chemical carcinogens, Cancer Res., 48:4578.PubMedGoogle Scholar
  19. Monk, M., Peacey, M., and Gross, J. D., 1971, Repair of damage induced by ultraviolet light in DNA polymerase defective Escherichia coli cells, J. Mol. Biol., 58:623.PubMedCrossRefGoogle Scholar
  20. Morais, R., 1980, On the effect of inhibitors of mitochondrial macromolecular synthesizing systems and respiration on the growth of cultures chick embryo, J. Cell. Phvsiol., 103:455.CrossRefGoogle Scholar
  21. Pelaprat, D., Delbarre, A., Le Guen, I., Roques, B. P., and Le Pecq, J.-B., 1980, DNA intercalating compounds as potential antitumor agents. 2. Preparation and properties of 7H-pyridocarbazole dimers, J. Med. Chem., 23:1336.PubMedCrossRefGoogle Scholar
  22. Quillardet, P., Huisman, O., d’Ari, R., and Hofnung, M., 1982, SOS chromotest, a direct assay of induction of an SOS function in E. coli K12 to measure genotoxicity, Proc. Natl. Acad. Sci. USA, 79:5971.PubMedCrossRefGoogle Scholar
  23. Roques, B. P., Pelaprat, D., Le Guen, I., Porcher, G., Gosse, Ch., and Le Pecq, J.-B., 1979, DNA bifunctional inter-calators. Antileukemic activities of new pyridocarbazole dimers, Biochem. Pharmacol., 28:1811.PubMedCrossRefGoogle Scholar
  24. Sancar, A., and Sancar, G.B., 1988, DNA repair enzymes, Ann. Rev. Biochem., 57:29.PubMedCrossRefGoogle Scholar
  25. Segal-Bendirdjian, E., Coulaud, D., Roques, B. P., and Le Pecq, J.-B., 1988, Selective loss of mitochondrial DNA after treatment of cells with Ditercalinium (NSC 335153), an antitumor bis-intercalating agent, Cancer Res., 40: 4982.Google Scholar
  26. Southern, E. M., 1975, Detection of specific sequences among DNA fragments separated by electrophoresis, J. Mol. Biol., 98:505.CrossRefGoogle Scholar
  27. Traganos, F., Bueti, C., Melamed, M. R., and Darzynkiewicz, Z., 1987, Cytokinetic effects of bifunctional antitumor intercalator Ditercalinium on Friend erythroleukemia cells, Leukemia (Baltimore), 1:411.Google Scholar
  28. Wakelin, L. P. G., 1986, Polyfunctional DNA intercalating agents, Med. Res. Rev., 6:275.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Bernard Lambert
    • 1
  • Evelyne Segal-Bendirdjian
    • 1
  • Bernard P. Roques
    • 2
  • Jean-Bernard Le Pecq
    • 1
  1. 1.Institut Gustave Roussy (URA158 CNRS, U140 INSERM)VillejuifFrance
  2. 2.University Paris V (UA498 CNRS, U226 INSERM)ParisFrance

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