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Topoisomerases, New Targets in Cancer Chemotherapy

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Abstract

The enzymes involved in the regulation of the three-dimensional structure of DNA, topoisomerase I and II, are important for the handling of DNA during vital cellular processes such as translation, transcription and mitosis. The enzymes are currently being studied intensively, they are being biochemically characterized and their mechanism of action is now better understood.

Empirically discovered antitumor drugs appear to interfere with these enzymes, especially topoisomerase II. The DNA-topoisomerase II complex, which is an intermediate in the normal enzyme pathway, is stabilized by the drug and forms a ‘cleavable complex’, which appears to be cytotoxic. The drugs involved are, e.g. anthra-cyclines, epipodophyllotoxins and acridines. The central role of this enzyme offers the cell an opportunity for the development of resistance by down-regulation of this enzyme or the production of resistant mutants, provided the adaptation does not hamper other vital cell functions.

Knowledge of the working mechanism and the cellular regulation of the topoisomerases might lead to the selection of most effective drugs and treatment schedules, and to circumvention of drug resistance.

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References

  1. 1.

    Epstein R J: Topoisomerases in human disease.Lancet i, 521 (1988).

  2. 2.

    Geliert M: DNA topoisomerases.Ann Rev Biochem 50, 879 (1981).

  3. 3.

    Wang J C: DNA topoisomerases.Ann Rev Biochem 54, 665 (1985).

  4. 4.

    Wang J C: Recent studies of DNA topoisomerases.Biochim Biophys Acta 909, 1 (1987).

  5. 5.

    Ross W E, Sullivan D M, Chow K-C: Altered function of DNA topoisomerases as a basis for antineoplastic drug action, in DeVita V T, Hellman S, Rosenberg S A (eds):Important Advances in Oncology 1988, Philadelphia, J. B. Lippincott (1988).

  6. 6.

    Thrash C, Bankier A T, Barell B G, Sternglanz R: Cloning, characterization and sequence of the yeast DNA topoisomerase I gene.Proc natn Acad Sci USA 82, 4374 (1985).

  7. 7.

    Goto T, Wang J C: Cloning of yeast TOP 1, the gene encoding DNA topoisomerase I, and construction of mutants defective in both DNA topoisomerase I and DNA topoisomerase II.Proc natn Acad Sci USA 82, 7178 (1985).

  8. 8.

    D’Arpa P, Machlin P S, Ratrie H, Rothfield N F, Cleveland D W, Earnshaw W C: cDNA cloning of human DNA topoisomerase I, catalytic activity of 67.7-k DNA carboxyl-terminal fragment.Proc natn Acad Sci USA 85, 2543 (1988).

  9. 9.

    Juan C-C, Hwang J, Liu A A, Whang-Peng J, Knutsen T, Huebner K, Croce C M, Zhang H, Wang J C, Liu L F: Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20ql2-13.2.Proc natn Acad Sci USA 85, 8910 (1988).

  10. 10.

    Riou J-F, Gabillot M, Philippe M, Schrevel J, Riou G: Purification and characterization ofPlasmodium berghei DNA topoisomerase I and II: drug action, inhibition of decatenation and relaxation, and stimulation of cleavage.Biochemistry 24, 1471 (1986).

  11. 11.

    Been M D, Burgess R R, Champoux J J: Nucleotide sequence preference at rat liver and wheat germ type 1 DNA topoisomerase breakage sites in duplex SV40 DNA.Nucl Acid Res 12, 3097 (1984).

  12. 12.

    Uemura T, Yanagida M: Isolation of type I and II DNA topoisomerase mutants from fission yeast: single and double mutants show different phenotypes in cell growth and chromatin organization.EMBO J 3, 1737 (1984).

  13. 13.

    Andoh T, Ishii K, Suzuki Y, Ikegami Y, Kusunoki Y, Takemoto Y, Okada K: Characterization of a mammalian mutant with camptothecin-resistant DNA topoisomerase L.Proc natn Acad Sci USA 84, 5565 (1987).

  14. 14.

    Zhang H, Wang J C, Liu L F: Involvement of DNA topoisomerase I in transcription of human ribosomal RNA genes.Proc natn Acad Sci USA 85, 1060 (1988).

  15. 15.

    Yang L, Wold M S, Li J J, Kelly T J, Liu L F: Roles of DNA topoisomerases in Simian Virus 40 DNA replicationin vitro.Proc natn Acad Sci USA 84, 950 (1987).

  16. 16.

    Javaherian K, Liu L F: Association of eukaryotic DNA topoisomerase I with nucleosomes and chromosomal proteins.Nucl Acid Res 11, 461 (1983).

  17. 17.

    Liu L F, Wang J C: Supercoiling of the DNA template during transcription.Proc natn Acad Sci USA 84, 7024 (1987).

  18. 18.

    Wang J C: DNA topoisomerases: from a laboratory curiosity to a subject in cancer chemotherapy, in Potmesil M, Ross W E (eds):Topoisomerases in Cancer Treatment. NCI Monograph 4. Bethesda, MD, National Cancer Institute (1987).

  19. 19.

    Tsai-Pflugfelder M, Liu L F, Liu A A, Tewey K M, Whang-Peng J, Knutsen T, Huebner K, Croce K M, Wang J C: Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22.Proc natn Acad Sci USA 85, 7177 (1988).

  20. 20.

    Uemura T, Morikawa K, Yanagida M: The nucleotide sequence of the fission yeast DNA topoisomerase II gene: structural and functional relationships to other DNA topoisomerases.EMBO J 5, 2355 (1986).

  21. 21.

    Lynn R, Giaever G, Swanberg S L, Wang J C: Tandem regions of yeast DNA topoisomerase II share homology with different subunits of bacterial gyrase.Science 233, 647 (1986).

  22. 22.

    Osheroff N, Shelton E R, Brutlag D L: DNA topoisomerase II fromDrosophila melanogaster.J biol Chem 258, 9536 (1983).

  23. 23.

    Miller K G, Liu L F, Englund P T: A homogeneous type II DNA topoisomerase from HeLa cell nuclei.J biol Chem 258, 9334 (1983).

  24. 24.

    Tewey K M, Chen G L, Nelson E M, Liu L F: Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.J biol Chem 259, 9182 (1984).

  25. 25.

    DiNardo S, Voelkel K, Sternglanz R: DNA topoisomerase II mutant ofSaccharomyces cerevisiae: topoisomerase II is required for segregation of daughter molecules at the termination of DNA replication.Proc natn Acad Sci USA 81, 2616 (1984).

  26. 26.

    Zhang L H, Mui S C, Todt J C, Strauss P R: Role for topoisomerases in the release of DNA into the detergent-soluble fraction of eukaryotic cells.Proc natn Acad Sci USA 83, 5871 (1986).

  27. 27.

    Holm C, Goto T, Wang J C, Botstein D: DNA topoisomerase II is required at the time of mitosis in yeast.Cell 41, 553 (1985).

  28. 28.

    Uemura T, Yanagida M: Mitotic spindle pulls but fails to separate chromosomes in type II DNA topoisomerase mutants: uncoordinated mitosis.EMBO J 5, 1003 (1986).

  29. 29.

    Hirose S, Suzuki Y:In vitro transcription of eukaryotic genes is affected differently by the degree of DNA supercoiling.Proc natn Acad Sci USA 85, 718 (1988).

  30. 30.

    Tsutsui K, Tsutsui K, Sakurai H, Shohmori T, Oda T: Levels of topoisomerase II and DNA polymerase a are regulated independently in developing neuronal nuclei.Biochem biophys Res Commun 138, 1116 (1986).

  31. 31.

    Nelson W G, Liu L F, Coffey D S: Newly replicated DNA is associated with DNA topoisomerase II in cultured rat prostatic adenocarcinoma cells.Nature 322, 187 (1986).

  32. 32.

    Mattern M R, Paone R F, Day III R S: Eukaryotic DNA repair is blocked at different steps by inhibitors of topoisomerases and of DNA polymerases a and ß.Biochim Biophys Acta 697, 6 (1982).

  33. 33.

    Tan K B, Mattern M R, Boyce R A, Schein P S: Elevated DNA topoisomerase II activity in nitrogen mustard-resistant human cells.Proc natn Acad Sci USA 84, 7668 (1987).

  34. 34.

    Downes C S, Johnson R T: DNA topoisomerases and DNA repair.Bio Essays 8, 179 (1988).

  35. 35.

    Darby M K, Herrera R E, Vosberg H-P, Nordheim A: DNA topoisomerase II cleaves at specific sites in the 5′ flanking region ofc-fos proto-oncogenesin vitro.EMBO J 5, 2257 (1986).

  36. 36.

    Udvardy A, Schedl P, Sander M, Hsieh T-S: Topoisomerase II cleavage in chromatin.J molec Biol 191, 231 (1986).

  37. 37.

    Gasser S M, Laroche T, Falquet J, Boy de la Tour E, Laemmli U K: Metaphase chromosome structure: involvement of topoisomerase IL.J molec Biol 188, 613 (1986).

  38. 38.

    Earnshaw W C, Halligan B, Cooke C A, Heck M M S, Liu L F: Topoisomerase II is a structural compound of mitotic chromosome scaffolds.J Cell Biol 100, 1706 (1985).

  39. 39.

    Berrios M, Osheroff N, Fisher F A:In situ localization of DNA topoisomerase II, a major polypeptide component of theDrosophila nuclear matrix fraction.Proc natn Acad Sci USA 82, 4142 (1985).

  40. 40.

    Hsiang Y-H, Wu H-Y, Liu L F: Proliferationdependent regulation of DNA topoisomerase II in cultured human cells.Cancer Res 48, 3230 (1988).

  41. 41.

    Heck M M S, Hittelman W N, Earnshaw W C: Differential expression of DNA topoisomerases I and II during the eukaryotic cell cycle.Proc natn Acad Sci USA 85, 1086 (1988).

  42. 42.

    Fairman R, Brutlag D L: Expression of theDrosophila type II topoisomerase is developmentally regulated.Biochemistry 27, 560 (1988).

  43. 43.

    Ackerman P, Glover C V C, Osheroff N: Phosphorylation of DNA topoisomerase II by casein kinase II: tmodulation of eukaryotic topoisomerase II activityin vitro.Proc natl Acad Sci USA 82, 3164 (1985).

  44. 44.

    Sahyoun N, Wolf M, Besterman J, Hsieh T-S, Sander M, Le Vine III H, Chang K-J, Cuatrecasas P: Protein kinase C phosphorylates topoisomerase II: topoisomerase activation and its possible role in phorbol ester-induced differentiation of HL-60 cells.Proc natn Acad Sci USA 83, 1603 (1986).

  45. 45.

    Darby M K, Smitt B, Jongstra-Bilen J, Vosberg H P: Inhibition of calf thymus type II DNA topoisomerase by poly (ADP-ribosilation).EMBO J 4, 2129 (1985).

  46. 46.

    Kohn K W, Ewig R A, Erickson L C, Zwelling L A: Measurement of strand breaks and cross links by alkaline elution, in Friedberg E C, Hanawalt P C (eds): DNA Repair: a Laboratory Manual of Research Procedures. New York, Marcel Dekker (1981).

  47. 47.

    Zwelling L A, Michaels S, Erickson L C, Ungerleider R S, Nichols M, Kohn K W: Proteinassociated deoxyribonucleic acid strand breaks in L1210 cells treated with the deoxyribonucleic acid intercalating agents 4′-(9-acri-dinylamino)methanesulfon-m-anisidide and adriamycin.Biochemistry 20, 6553 (1981).

  48. 48.

    Nelson E M, Tewey K M, Liu L F: Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4′-(9-acridinylamino)-methanesulfon-m-aniside.Proc natn Acad Sci USA 81, 1361 (1984).

  49. 49.

    Ross W E, Glaubiger D L, Kohn K W: Proteinassociated DNA breaks in cells treated with adriamycin or ellipticin.Biochim biophys Acta 519, 23 (1979).

  50. 50.

    Ross W E, Glaubiger D L, Kohn K W: Qualitative aspects of intercalator-induced DNA strand breaks.Biochim biophys Acta 562, 41 (1979).

  51. 51.

    Kanter P M, Schwartz H S: A fluorescence enhancement assay for cellular DNA damage.Molec Pharmac 22, 145 (1982).

  52. 52.

    Weniger P: An improved method to detect small amounts of radiation damage in DNA of eukaryotic cells.Int J radiat Biol 36, 197 (1979).

  53. 53.

    Trask D K, DiDonato J A, Muller M T: Rapid detection and isolation of covalent DNA/protein complexes: application to topoisomerase I and II.EMBO J 3, 671 (1984).

  54. 54.

    Liu L F, Rowe T C, Yang L, Tewey K M, Chen G L: Cleavage of DNA by mammalian DNA topoisomerase IL.J biol Chem 258, 15, 365 (1983).

  55. 55.

    Hsiang Y-H, Herzberg R, Hecht S, Liu L F: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I.J biol Chem 260, 14, 873 (1985).

  56. 56.

    Liu L F, Davis J L, Calendar R: Novel topologically knotted DNA from bacteriophage P4 capsids: studies with topoisomerases.Nucl Acids Res 9, 3979 (1981).

  57. 57.

    Marini J C, Miller K G, Englund P T: Decatenation of kinetoplast DNA by topoisomerase II.J biol Chem 255, 4976 (1980).

  58. 58.

    Tsuruo T, Matsuzaki T, Matsushita M, Saito H, Yokokura T: Antitumor effect on CPT-11, a new derivative of camptothecin, against pleiotropic drugresistant tumorsin vitro andin vivo.Cancer Chemother Pharmac 21, 71 (1988).

  59. 59.

    Sullivan D M, Latham M D, Ross W E: Proliferation-dependent topoisomerase II content as a determinant of antineoplastic drug action in human, mouse and Chinese hamster ovary cells.Cancer Res 47, 3973 (1987).

  60. 60.

    Nelson W G, Cho K R, Hsiang Y-H, Liu L F, Coffey D S: Growth-related elevations of DNA topoisomerase II levels found in Dunning R3327 rat prostatic adenocarcinomas.Cancer Res 47, 3246 (1987).

  61. 61.

    Drake F H, Zimmerman J P, McCabe F L, Bartus H F, Per S R, Sullivan D M, Ross W E, Mattern M R, Johnson R K, Crooke S T, Mirabelli C K: Purification of topoisomerase II from amsacrineresistant P388 leukemia cells.J biol Chem 262, 16739 (1987).

  62. 62.

    Drlica K, Franco R J: Inhibitors of DNA topoisomerases.Biochemistry 27, 2253 (1988).

  63. 63.

    Hsiang Y-H, Liu L F: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin.Cancer Res 48, 1722 (1988).

  64. 64.

    Avemann K, Knippers R, Koller T, Sogo J M: Camptothecin, a specific inhibitor of type I DNA topoisomerase induces DNA breakage at replication forks.Molec Cell Biol 8, 3026 (1988).

  65. 65.

    Gottlieb J A, Guarino A M, Call J B: Preliminary pharmacologic and clinical evaluation of camptothecin (NSC-100880).Cancer Chemother Rep 54, 461 (1970).

  66. 66.

    Ishii K, Futaki S, Uchiyama H, Nagasawa K, Andoh T: Mechanism of inhibition of mammalian DNA topoisomerase I by heparin.Biochem J 241, 111 (1987).

  67. 67.

    Pommier Y, Covey J M, Kerrigan D, Markovits J, Pham R: DNA unwinding and inhibition of mouse leukemia L1210 DNA topoisomerase I by intercalators.Nucl Acids Res 15, 6713 (1987).

  68. 68.

    Trask D K, Muller M T: Stabilization of type I topoisomerase-DNA covalent complexes by actinomycin D.Proc natn Acad Sci USA 85, 1417 (1988).

  69. 69.

    Ross W E: DNA topoisomerases as targets for cancer therapy.Biochem Pharmac 34, 4191 (1985).

  70. 70.

    Yang L, Rowe T C, Liu L F: Identification of DNA topoisomerase II as an intracellular target of antitumor epipodophyllotoxins in Simian Virus 40-infected monkey cells.Cancer Res 45, 5872 (1985).

  71. 71.

    Rowe T, Kupfer G, Ross W: Inhibition of epipodophyllotoxin cytotoxicity by interference with topoisomerase-mediated DNA cleavage.Biochem Pharm 34, 2483 (1985).

  72. 72.

    Chen G L, Yang L, Rowe T C, Halligan B D, Tewey K M, Liu L F: Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.J biol Chem 259, 13560 (1984).

  73. 73.

    Ross W, Rowe T, Glisson B, Yalowich J, Liu L: Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage.Cancer Res 44, 5857 (1984).

  74. 74.

    Tewey K M, Rowe T C, Yang L, Halligan B D, Liu L F: Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II.Science 226, 466 (1984).

  75. 75.

    Crespi M D, Ivanier S E, Genovese J, Baldi A: Mitoxantrone affects topoisomerase activities in human breast cancer cells.Biochem biophys Res Commun 136, 521 (1986).

  76. 76.

    Vilarem M-J, Gras M-P, Larsen C-J: BD40, an ellipticine-related DNA intercalative agent induces DNA-protein bridgesin vivo.Nucl Acids Res 12, 8653 (1984).

  77. 77.

    Ross W E, Bradley M O: DNA double-stranded breaks in mammalian cells after exposure to intercalating agents.Biochim biophys Acta 654, 129 (1981).

  78. 78.

    Zwelling L A, Kerrigan D, Michaels S, Kohn K W: Cooperative sequestration of m-AMSA in L1210 cells.Biochem Pharmac 31, 3269 (1982).

  79. 79.

    Rowe T C, Chen G L, Hsiang Y-H, Liu L F: DNA damage by antitumor acridines mediated by mammalian DNA topoisomerase II.Cancer Res 46, 2021 (1986).

  80. 80.

    Epstein R J, Smith P J: Estrogen-induced potentiation of DNA damage and cytotoxicity in human breast cancer cells treated with topoisomerase II-interactive antitumor drugs.Cancer Res 48, 297 (1988).

  81. 81.

    Robbie M A, Baguley B C, Denny W A, Gavin J B, Wilson W R: Mechanism of resistance of noncycling mammalian cells to 4′-(9-acridinylamino)methanosulfon-m-anisidide: comparison of uptake, metabolism, and DNA breakage in log- and plateauphase Chinese hamster fibroblast cell cultures.Cancer Res 48, 310 (1988).

  82. 82.

    Pommier Y, Zwelling L A, Kao-Shan C-S, WhangPeng J, Bradley M O: Correlation between intercalator-induced DNA strand breaks and sister chromatid exchanges, mutations, and cytotoxicity in Chinese hamster cells.Cancer Res 45, 3143 (1985).

  83. 83.

    Zwelling L A, Estey E, Silberman L, Doyle S, Hittelman W: Effect of cell proliferation and chromatin conformation on intercalator-induced, protein-associated DNA cleavage in human brain tumor cells and human fibroblasts.Cancer Res 47, 251 (1987).

  84. 84.

    Chow K-C, Ross W E: Topoisomerase-specific drug sensitivity in relation to cell cycle progression.Molec Cell Biol 7, 3119 (1987).

  85. 85.

    Estey E, Adlakha R C, Hittelman W N, Zwelling L A: Cell cycle stage dependent variations in druginduced topoisomerase II mediated DNA cleavage and cytotoxicity.Biochemistry 26, 4338 (1987).

  86. 86.

    Pommier Y, Schwartz R E, Zwelling L A, Kerrigan D, Mattern M R, Charcosset J Y, Jacquemin-Sablon A, Kohn K W: Reduced formation of proteinassociated DNA strand breaks in Chinese hamster cells resistant to topoisomerase II inhibitors.Cancer Res 46, 611 (1986).

  87. 87.

    Bae Y S, Kawasaki J, Ikeda H, Liu L F: Illegitimate recombination mediated by calf thymus DNA topoisomerase IIin vitro.Proc natn Acad Sci USA 85, 2076 (1988).

  88. 88.

    Pommier Y, Kerrigan D, Covey J M, Kao-Shan C-S, Whang-Peng J: Sister chromatid exchanges, chromosomal aberrations, and cytotoxicity produced by antitumor topoisomerase II inhibitors in sensitive (DC3F) and resistant (DC3F/9-OHE) Chinese hamster cells.Cancer Res 48, 512 (1988).

  89. 89.

    Dillehay L E, Denstman S C, Williams J R: Cell cycle dependence of sister chromatid exchange induction by DNA topoisomerase II inhibitors in Chinese hamster V79 cells.Cancer Res 47, 206 (1987).

  90. 90.

    Heck M M S, Earnshaw W C: Topoisomerase II: a specific marker for cell proliferation.J Cell Biol 103, 2569 (1986).

  91. 91.

    Markovits J, Pommier Y, Kerrigan D, Covey J M, Tilchen E J, Kohn K W: Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells.Cancer Res 47, 2050 (1987).

  92. 92.

    Kjeldsen E, Bonven B J, Andoh T, Ishii K, Okada K, Bolund L, Westergaerd O: Characterization of a camptothecin-resistant human DNA topoisomerase I.J biol Chem 263, 3912 (1988).

  93. 93.

    Gupta R S, Gupta R, Eng B, Lock R B, Ross W E, Hertzberg R P, Caranfa M J, Johnson R K: Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I.Cancer Res 48, 6404 (1988).

  94. 94.

    Glisson B, Gupta R, Hodges P, Ross W: Crossresistance to intercalating agents in an epipodophyllotoxin-resistant Chinese hamster ovary cell line: evidence for a common intracellular target.Cancer Res 46, 1939 (1986).

  95. 95.

    Pommier Y, Kerrigan D, Schwarts R E, Swack J A, McCurdy A: Altered DNA topoisomerase II activity in Chinese hamster cells resistant to topoisomerase II inhibitors.Cancer Res 46, 3075 (1986).

  96. 96.

    Long B H, Musial S T, Brattain M G: DNA breakage in human lung carcinoma cells and nuclei that are naturally sensitive or resistant to etoposide and teniposide.Cancer Res 46, 3809 (1986).

  97. 97.

    Robson C N, Hoban P R, Harris A L, Hickson I D: Cross-sensitivity to topoisomerase II inhibitors in cytotoxic drug-hypersensitive Chinese hamster ovary cell lines.Cancer Res 47, 1560 (1987).

  98. 98.

    Estey E H, Silberman L, Beran M, Andersson B S, Zwelling L A: The interaction between nuclear topoisomerase II activity from human leukemia cells, exogenous DNA, and 4′-(9-acridinylamino) methanesulfon-m-aniside (m-AMSA) or 4-(4,6-O-ethylidene-ß-D-glucopyranoside) (VP-16) indicates the sensitivity of the cells to the drugs.Biochem biophys Res Commun 47, 787 (1987).

  99. 99.

    Zijlstra J G, de Vries E G E, Mulder N H: Multifactorial drug resistance in an adriamycinresistant human small cell lung carcinoma cell line.Cancer Res 47, 1780 (1987).

  100. 100.

    Danks M K, Yalowich J C, Beck W T: Atypical multiple drug resistance in a human leukemic cell line selected for resistance to teniposide (VM 26).Cancer Res 47, 1297 (1987).

  101. 101.

    Glisson B, Gupta R, Smallwood-Kentro S, Ross W: Characterization of acquired epipodophyllotoxin resistance in a Chinese hamster ovary cell line: loss of drug-stimulated DNA cleavage activity.Cancer Res 46, 1934 (1986).

  102. 102.

    Ferguson P J, Fisher M H, Stephenson J, Li D, Zhou B, Cheng Y: Combined modalities of resistance in etoposide-resistant human KB cell lines.Cancer Res 48, 5956 (1988).

  103. 103.

    Per S R, Mattern M R, Mirabelli C K, Drake F H, Johnson R K, Crooke S T: Characterization of a subline of P388 leukemia resistant to amsacrine: evidence of altered topoisomerase II function.Molec Pharmac 32, 17 (1987).

  104. 104.

    Dorr R T, Liddil J D, Gerner E W: Modulation of etoposide cytotoxicity and DNA strand scission in L1210 and 8226 cells by polyamines.Cancer Res 46, 3891 (1986).

  105. 105.

    Zwelling L A, Kerrigan D, Marton L J: Effect of difluoromethylornithine, an inhibitor of polyamine biosynthesis on the topoisomerase II-mediated DNA scission produced by 4′-(9-acridinylamino) methanesulfon-m-anisidide in L1210 murine leukemia cells.Cancer Res 45, 1122 (1985).

  106. 106.

    Alexander R B, Nelson W G, Coffey D S: Synergistic enhancement by tumor necrosis factor ofin vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II.Cancer Res 47, 2403 (1987).

  107. 107.

    Zwelling L A, Chan D, Hinds M, Mayes J, Silberman L E, Blick M: Effect of phorbol ester treatment on drug-induced topoisomerase II-mediated DNA cleavage in human leukemia cells.Cancer Res 48, 6625 (1988).

  108. 108.

    Miskimins R, Miskimins W K, Bernstein H, Shimizu N: Epidermal growth factor-induced topoisomerase(s).Exp Cell Res 146, 53 (1983).

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Zijlstra, J.G., DE Jong, S., DE Vries, E.G.E. et al. Topoisomerases, New Targets in Cancer Chemotherapy. Med. Oncolo. & Tumor Pharmacother. 7, 11–18 (1990). https://doi.org/10.1007/BF03000485

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Key words

  • Topoisomerase
  • Drug resistance