Pharmacology of DNA Binding Drugs

  • Bernard Lambert
  • Jean-Bernard Le Pecq
Part of the NATO ASI Series book series (volume 137)


Many compounds from various sources have been found able to bind to nucleic acids. Among those are numerous basic dyes used to stain the chromatin in the cell nucleus, several antibiotics, plant alcaloïds and various chemicals synthetized during the last fifty years. Several of these compounds have useful pharmacological properties and are used in human and veterinary medicine for the treatment of parasitic diseases (rev. Van den Bossche, 1978). and cancers (rev. Le Pecq, 1978; Pratt and Ruddon, 1979). All these chemicals act by killing or preventing specifically the growth of target cells. A limited list of the most important derivatives is given in Table 1 with their corresponding structures shown in Figure 1.


Intercalate Agent Chinese Hamster Lung Cell dnaB Protein Mouse Leukemia L1210 Cell Protein Associate Break 
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  1. Arai, K.I., and Kornberg, A., 1981, Mechanism of dnaB protein action III allosteric role of ATP in the alteration of DNA structure by dnaB protein in priming replication, J. Biol. Chem., 256:5260–5266.PubMedGoogle Scholar
  2. Bendirdjian, J-P., Delaporte, C., Roques, B. P., and Jacquemin-Sablon, A., 1984, Effects of 7H-pyridocarbazole mono and bifunctional DNA-intercalators on Chinese hamster lung cells in vitro, Biochem. Pharmacol., 33:3681–3688.PubMedCrossRefGoogle Scholar
  3. Charcosset, J-Y., Salles, B., and Jacquemin-Sablon, A., 1983, Uptake and cytofluorescence localization of ellipticine derivatives in sensitive and resistant Chinese hamster lung cells, Biochem. Pharmacol., 32:1037–1044.PubMedCrossRefGoogle Scholar
  4. Charcosset, J-Y., Bendirdjian, J-P., Lantieri, M-F., and Jacquemin-Sablon, A., 1985, Effects of 9-hydroxyellipticine on cell survival, macromolecular synthesis, and cell cycle progression in sensitive and resistant Chinese hamster lung cells, Cancer Res., 45:4229–4236.PubMedGoogle Scholar
  5. Chen, G.L., Yang, L., Rowe, T.C., Halligan, B.D., Tewey, K.M., and Liu, L.F., 1984, Non intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II, J. Biol. Chem., 259:13560–13566.PubMedGoogle Scholar
  6. Chen, L.B., Weiss, M.J., Davis, S., Bleday, R.S., Wong, J.R., Song, J., Terasaki, M., Shepherd, E.L., Walker, E.S., and Steele, Jr. G.D., 1985, in: “Cancer Cells 3.-growth factors and transformation”, J. Feramisco, B. Ozanne and Ch. Stiles eds. Cold Spring Harbor laboratories publ. pp.433-443.Google Scholar
  7. Denny, W.A., Baguley, B.C., Cain, B.F., and Waring, M.J., 1983, Antitumor acridines, in: “Molecular aspects of anti-cancer drug action”, Neidle S. and Waring M.J. ed., Verlag Chemie Publ., p.1-34.Google Scholar
  8. Douc-Rasy, S., Kayser, A., and Riou, G., 1984, Inhibition of the reactions catalysed by a type I topoisomerase and a catenating enzyme of Trypanosoma cruzi by DNA-intercalating drugs. Preferential inhibition of the catenating reaction, The EMBO J., 3:11–16.Google Scholar
  9. Douc-Rasy, S., Kayer, A., Riou, J.F., and Riou, G., 1986, ATP-independent type II topoisomerase from trypanosomes, Proc. Natl. Acad. Sci. USA, in press.Google Scholar
  10. Esnault, C., Roques, B.P., Jacquemin-Sablon, A., and Le Pecq, J.B., 1984, Effects of new antitumor bifunctional intercalators derived from 7H-pyridocarbazole on sensitive and resistant L1210 cells, Cancer Res., 44:4335–4360.Google Scholar
  11. Fairfield, F.R., Bauer, W.R., and Simpson, M.V., 1985, Studies on mitochondrial type I topoisomerase and on its function, Biochim. Biophys. Acta, 824:45–57.PubMedCrossRefGoogle Scholar
  12. Glisson, B., Gupta, R., Hodges, P., and Ross, W., 1986a, Characterization of acquired Epipodophyllotoxin resistance in a Chinese hamster ovary cell line: Loss of drug-stimulated DNA cleavage activity, Cancer Res., 46:1934–1938.PubMedGoogle Scholar
  13. Glisson, B., Gupta, R., Hodges, P., and Ross, W., 1986b, Cross resistance to intercalating agents in a epipodophyllotoxin-resistant hamster ovary cell line: Evidence for a common intracellular target, Cancer Res., 46:1939–1942.PubMedGoogle Scholar
  14. Huisman, O., and D’Ari, R., 1981, An inducible DNA replication cell division coupling mechanism in E.coli, Nature, 290:727–799.CrossRefGoogle Scholar
  15. Lambert, B., and Le Pecq, J.B., 1982, Isolement et caractérisation de souches d’E.coli sensibles à des toxiques hydrophiles et/ou chargés, C. R. Acad. Sci. Paris, 294:447–450.Google Scholar
  16. Lambert, B., Laugaa, Ph., Roques, B.P., and Le Pecq, J.B., 1986, Cytotoxicity and SOS inducing ability of ethidium and photoactivable analogs on E.coli ethidium sensitive (Ebs) strains, Mutation Res., in press.Google Scholar
  17. Laugaa, 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. Kinetics studies, Biochemistry, 24:5567–5575.PubMedCrossRefGoogle Scholar
  18. Le Pecq, J.B., 1978, “Chimiothérapie anticancéreuse”, Hermann Publ., Paris.Google Scholar
  19. Le Pecq, J.B., 1982, Spécificité d’action des substances antitumorales, J. Pharmacol., 13:53–75.PubMedGoogle Scholar
  20. Le Pecq, J.B., Dat-Xuong, N., Gosse, Ch., and Paoletti, C., 1974, A new antitumoral agent: 9 hydroxyellipticine. Possibility of a rational design of anticancerous drugs in the series of DNA interacting: drugs, Proc. Natl. Acad. Sci. USA, 71:5078–5082.PubMedCrossRefGoogle Scholar
  21. 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”, Simic M.G., Grossman L. and Upton A.C. ed., Plenum Press Publ., New York, p.219–230.CrossRefGoogle Scholar
  22. 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 topoisomerase II, Cancer Res., in press.Google Scholar
  23. Mindford, J., Pommier, Y., Filipski, J., Kohn, K., Derrigan, D., Mattern, M.R., Michaels, S., Schwartz, R., and Zwelling, L., 1986, Isolation of interalator-dependent protein linked DNA strand cleavage activity from cell nuclei and identification as topoisomerase II, Biochemistry, 25:9–16.CrossRefGoogle Scholar
  24. Nelson, E.M., Tewey, K.M., and Liu, L.F., 1984, Mechanism of antitumor drug action: Poisoning of mammalian DNA topoisomerase II on DNA by 4′-(9-acridinylamino)-methane sulfon-m-anisidide, Proc. Natl. Acad. Sci. USA, 81:1361–1365.PubMedCrossRefGoogle Scholar
  25. Paoletti, C., Lesca, C., Cros, S., Malvy, C., and Auclair, C., 1979, Ellipticine and derivatives induce breakage of L1210 DNA in vitro, Biochem. Pharmacol., 28:345–350.PubMedCrossRefGoogle Scholar
  26. 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., 23:1336–1343.PubMedCrossRefGoogle Scholar
  27. Pommier, Y., Mattern, M.R., Schwartz, R.E., and Zwelling, L.A., 1984a, Absence of swiveling at sites of intercalator-induced protein-associated deoxyribonucleic acid strand breaks in mammalian cells nucleoïds, Biochemistry, 23:2922–2927.PubMedCrossRefGoogle Scholar
  28. Pommier, Y., Schwartz, R.E., Kohn, K.W., and Zwelling, L.A., 1984b, Formation and rejoining of deoxyribonucleic acid double-strand breaks induced in isolated cell nuclei by antineoplastic intercalating agents, Biochemistry, 23:3194–3201.PubMedCrossRefGoogle Scholar
  29. Pommier, Y., Zwelling, L.A., Kao-Shan, C.S., Whang-Peng, J., and Bradley, M., 1985, Correlation between intercalator-induced DNA strand breaks and sister chromatid exchanges, mutations and cytotoxicity in Chinese hamster cells, Cancer Res., 45:3143–3147.PubMedGoogle Scholar
  30. Pommier, Y., Schwartz, R.E., Zwelling, L., Kerrigan, D., Mattern M., Charcosset, J.Y., Jacquemin-Sablon, A., and Kohn, K., 1986a, Reduced formation of protein-associated DNA strand breaks in Chinese hamster cells resistant to topoisomerase II inhibitors, Cancer Res., 46:611–616.PubMedGoogle Scholar
  31. Pommier, Y., Kerrigan, D., Schwartz, R., Swack, J.A., and McCurdy, A., 1986b, Altered DNA topoisomerase II activity in Chinese hamster cells resistant to topoisomerase II inhibitors, Cancer Res., 46:3075–3081.PubMedGoogle Scholar
  32. Povirk, L.F., Hogan, M., and Dattagupta, N., 1979, Binding of Bleomycin to DNA: Intercalation of the bithiazole rings, Biochemistry, 18:96–101.PubMedCrossRefGoogle Scholar
  33. Pratt, W., and Ruddon, R., 1979, “The Anticancer Drugs”, Oxford University Press Publ., New York.Google Scholar
  34. Quigley, G.J., Ughetto, G., van der Marel, G.A., van Boom, J.H., Wang, A.H.J., and Rich, A., 1986, Non-Watson-Crick G.C and A.T base pairs in a DNA-antibiotic complex, Science, 232:1255–1258.PubMedCrossRefGoogle Scholar
  35. Rao, P.N., 1979, G2 arrest induced by anticancer drug, in “Effects of drugs on the cell nucleus”, H. Busch, S.T. Crooke and Y. Daskal ed., Academic Press, New York, p.475–490.Google Scholar
  36. Riou, J.F., Multon, E., Vilarem, M.J., Larsen, Ch., and Riou, G., 1986a, In vivo Stimulation by antitumor drugs of the topoisomerase II induced cleavage sites in c-myc protooncogène, Biochem. Biophys. Res. Comm., 137:154–160.PubMedCrossRefGoogle Scholar
  37. Riou, J.F., Vilarem, M.J., Larsen, C.J., and Riou, G., 1986b, Characterization of the topoisomerase II-induced cleavage sites in the c-myc protooncogene: in vitro stimulation by the antitumoral intercalating drug mAMSA, Biochem. Pharmacol., in press.Google Scholar
  38. Riou, J.F., Gabillot, M., Philippe, M., Schrevel, J., and Riou, G., 1986c, Purification and characterization of plasmodium berghei DNA topoisomerase I and II: Drug action inhibition of decatenation and relaxation, and stimulation of DNA cleavage, Biochemistry, 25:1471–1479.PubMedCrossRefGoogle Scholar
  39. Roques, B.P., Pelaprat, D., Le Guen, I., Porcher, G., Gosse, Ch., and Le Pecq, J.B., 1979, DNA bifunctional intercalators. Antileukemic activities of new pyridocarbazole dimers, Biochem. Pharmacol., 28, 1811–1815.PubMedCrossRefGoogle Scholar
  40. Ross, W.E., 1985, DNA topoisomerases as targets for cancer therapy, Biochem. Pharmacol., 34:4191–4195.PubMedCrossRefGoogle Scholar
  41. Ross, W.E., and Bradley, M.O., 1981, DNA double-strand breaks in mammalian cells after exposure to DNA intercalating agents, Biochim. Biophys. Acta, 654:129–134.PubMedCrossRefGoogle Scholar
  42. Ross, W.E., and Smith, M.C., 1982, Repair of deoxyribonucleic acid lesions caused by adriamycin and ellipticine, Biochem. Pharmacol., 31:1931–1935.PubMedCrossRefGoogle Scholar
  43. Ross, W.E., Glaubiger, D.L., and Kohn, K.W., 1978, Protein-associated DNA breaks in cell treated with adriamycin and ellipticine, Biochim. Biophys. Acta, 519:23–30.PubMedCrossRefGoogle Scholar
  44. Ross, W.E., Glaubiger, D.L., and Kohn, K.W., 1979, Qualitative and quantitative aspects of intercalator-induced DNA strand breaks, Biochim. Biophys. Acta, 562:41–50.PubMedCrossRefGoogle Scholar
  45. Ross, W., Rowe, T., Glisson, B., Yalowich, J., and Liu, L., 1984, Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage, Cancer Res., 44:5857–5860.PubMedGoogle Scholar
  46. Rowe, T., Kupfer, G., and Ross, W., 1985, Inhibition of epipodophyllotoxin cytotoxicity by interference with topoisomerase-mediated DNA cleavage, Biochem. Pharmacol., 34:2483–2487.PubMedCrossRefGoogle Scholar
  47. Rowe, T., Chen, G., and Liu, L., 1986a, DNA damage by antitumor acridines mediated by mammalian DNA topoisomerase II, Cancer Res., 46:2021–2026.PubMedGoogle Scholar
  48. Rowe, T., Wang, J.C., and Liu, L., 1986b, In vivo localization of DNA topoisomerase II cleavage sites on Drosophila heat shock chromatin, Molecular and Cellular Biology, 6:985–992.PubMedGoogle Scholar
  49. Salles, B., Charcosset, J.Y., and Jacquemin-Sablon, A., 1982, Isolation and properties of Chinese hamster lung cells resistant to ellipticine derivatives, Cancer Treat. Rep., 66:327–338.PubMedGoogle Scholar
  50. Tewey, K., Chen, G., Nelson, E., and Liu, L., 1984, Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II, J. Biol. Chem., 259:9182–9187.PubMedGoogle Scholar
  51. Tritton, T.R., and Yee, G., 1982, The antitumor agent adriamycin can be actively cytotoxic without entering cells, Science, 217:248–250.CrossRefGoogle Scholar
  52. Umezawa, H., 1976, Bleomycin: Discovery, chemistry and action, Gann, 19:3–36.Google Scholar
  53. Van den Bossche, H., 1978, Chemotherapy of parasitic infections, Nature, 273:626–630.PubMedCrossRefGoogle Scholar
  54. Wang, J.C., 1985, DNA topoisomerases, Ann. Rev. Biochem., 54:665–697.PubMedCrossRefGoogle Scholar
  55. Waring, M.J., 1981, DNA modification and cancer, Ann. Rev. Biochem., 50:159–192.PubMedCrossRefGoogle Scholar
  56. Wilson, W.D., and Jones, R.L., 1981, Intercalating drugs: DNA binding and molecular pharmacology, Adv. Pharmacol. Chemother., 18:177–222.PubMedCrossRefGoogle Scholar
  57. Yang, L., Rowe, R.C., Nelson, E.M., and Liu, L., 1985, In vivo mapping of DNA topoisomerase II-specific cleavage sites on SV40 chromatin, Cell, 41:127–132.PubMedCrossRefGoogle Scholar
  58. Zimmer, Ch., and Wähnert, U., 1986, Nonintercalating DNA-binding ligands: specificity of the interaction and their use as tools in biophysical, biochemical and biological investigations of the genetic material, Prog. Biophys. Molec. Biol., 47:31–112.CrossRefGoogle Scholar
  59. Zwelling, L., Michaels, S., Erickson, L., Ungerleider, R.S., Nichols, M., and Kohn, K.W., 1981, Protein associated deoxyribonucleic acid strand breaks in L1210 cells treated with the deoxyribonucleic intercalating agents 4′-(9-acridiny1amino)methanesulfon-m-anisidide and adriamycin, Biochemistry, 20:6553–6563.PubMedCrossRefGoogle Scholar
  60. Zwelling, L., Michaels, S., Kerrigan, D., Pommier, Y., and Kohn, K., 1982, Protein-associated deoxyribonucleic acid strand breaks produced in mouse leukemia L1210 cells by ellipticine and 2-methyl-9-hydroxyellipticinium, Biochem. Pharmacol., 31:3261–3267.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Bernard Lambert
    • 1
  • Jean-Bernard Le Pecq
    • 1
  1. 1.Laboratoire de Pharmacologie Moléculaire (UA n°147 CNRS, U n°140 INSERM)Institut Gustave-Roussy, Rue Camille DesmoulinsVillejuif, CedexFrance

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