Topoisomerase II as a target for anticancer chemotherapy

• Autorzy: Kaufmann S. H. , Hancock R.
• Języki publikacji: EN

Abstrakty

EN

Type II DNA topoisomerases are required for the segregation of genomic DNA at cell division in prokaryotic and eukaryotic cells, and inhibitors of these enzymes are potential cytotoxic agents in both prokaryotes and eukaryotes. The bacterial member of the topoisomerase II family, DNA gyrase, and the chemotherapeutic agents which target it are the subject of a recent review (Maxwell, A. et al., 1993, in Molecular Biology of DNA Topoisomerases, Andoh, T. et al., eds.,pp. 21-30, CRC Press, Boca Raton). Here we present an overview of current knowledge of eukaryotic topoisomerase II and the anticancer agents which target this enzyme, focussing predominantly on new observations and recent reports and reviews.

Słowa kluczowe

EN

anticancer drug; eukaryotic cell; anticancer chemotherapy; cytotoxic agent; DNA; topoisomerase II; inhibitor; prokaryotic cell

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 1995
• Tom: 42
• Numer: 4
• Opis fizyczny: p.381-393,fig.

Twórcy

autor

Kaufmann S. H.

• Mayo Clinic, Rochester, Minnesota 55905, USA

autor

Hancock R.

Bibliografia

• 1. Maxwell, A., Ali,J.A., Bates, A.D., Contreras, A., Howells, A.J., Jackson, A.P., Reece, R.J., Will- mott, C.J.R., Davies, G.J. & Wigley, D.B. (1993) DNA gyrase: structure, mechanism, and inter­action with antibiotics; in Molecular Biology of DNA Topoisomerases (Andoh, T., Iked a, H. & Oguro, M., eds.) pp. 21-30, CRC Press, Boca Raton.
• 2. Caron, P.R. & Wang, J.C. (1993) DNA topoiso­merases a targets of therapeutics: a structural overview; in Molecular Biology of DNA Topo­isomerases (Andoh, T., Ikeda, H. & Oguro, M., eds.) pp. 1-18, CRC Press, Boca Raton.
• 3. Osheroff, N., Corbett, A.H. & Robinson, M.J. (1994) Mechanism of action of topoisomerase II-targeted antineoplastic drugs. Adv. Pharmacol. 29B, 105-126.
• 4. Drake, F.H., Hofmann, G.H., Mong, S-, Bartus, H.F., Per, S.R., Sullivan, D.M., Ross, W.E., Mattern, M.R., Johnson, R.K., Crooke, S.T. & Mirabelli, C.K. (1987) Purification of topo­isomerase II from amsacrine-resistant P388 cells: evidence for two forms of the enzyme. /. Biol Chem. 262,16739-16747.
• 5. Tsutsui, K., Tsutsui, K., Okada, S., Shohmori, T. & Seki, S. (1993) Differential expression of DNA topoisomerase II isozymes in developing rat brain; in Molecular Biology of DNA Topoisomerases (Andoh, T., Ikeda, H. & Oguro, M., eds.) pp. 115-131, CRC Press, Boca Raton.
• 6. Juenka, J.M. & Holden, J.A. (1993) The distri­bution of DNA topoisomerase II isoforms in differentiated adult mouse tissues. Biochim. Biophys. Acta 1216,191-196.
• 7. Enomoto, T., Saijo, M., Kimura, K. & Ui, M. (1993) Cell cycle-dependent phosphorylation of DNA topoisomerase II and modification of its activity by phosphorylation; in Molecular Biolo­gy of DNA Topoisomerases (Andoh, T., Ikeda, H. & Oguro, M., eds.) pp. 66-75, CRC Press, Boca Raton.
• 8. Kimura, K„ Nozaki, N., Saijo, M., Kikuchi, A., Ui, M. & Enomoto, T. (1994) Identification of the nature of modification that causes the shift of DNA topoisomerase lip to apparent higher molecular weight forms in the M phase. ]. Biol. Chem. 269,24523-24526.
• 9. Burden, D.A. & Sullivan, D.M. (1994) Phospho­rylation of the a- and P-isoforms of DNA topo­isomerase II is qualitatively different in inter­phase and mitosis in Chinese hamster ovary cells. Biochemistry 33,14651-14655.
• 10. Shiozaki, K. & Yanagida, M. (1992) Functional dissection of the phosphorylated termini of fission yeast DNA topoisomerase II. /. Cell. Biol. 119,1023-1036.
• 11. Roca, J. & Wang, J.C. (1992) The capture of a DNA double helix by an ATP-dependent pro­tein clamp: a key step in DNA transport by type II DNA topoisomerases. Cell 71,833-840.
• 12. Nitiss, J.L. (1994) Yeast as a genetic model sys­tem for studying topoisomerase II inhibitors. Adv. Pharmacol. 29B, 201-226.
• 13. Wasserman, R. & Wang, J.C. (1994) Mechanistic studies of amsacrine-resistant derivatives of DNA topoisomerase II. J. Biol. Chem. 269, 20943-20951.
• 14. Roca, ]., Ishida, R., Berger, J.M., Andoh, T. & Wang, J.C. (1994) Antitumor bisdioxopipera- zines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc. Natl. Acad. Sci. U.S.A. 91, 1781-1785.
• 15. Elsea, S.H., Hsiung, Y„ Nitiss,J.L. & Osheroff, N. (1995) A yeast type II topoisomerase selected for resistance to quinolones. J. Biol. Chem. 270, 1913-1920.
• 16. Uemura, T., Ohkura, H., Adachi, Y., Morino, K„ Shiozaki, K. & Yanagida, M. (1987) DNA topo­isomerase II is required for condensation and separation of mitotic chromosomes in S. pombe. Cell 50,917-925.
• 17. Charron, M. & Hancock, R. (1990) DNA topo­isomerase II is required for formation of mitotic chromosomes in CHO cells: studies using the inhibitor VM-26. Biochemistry 29,9531-9537.
• 18. Charron, M. & Hancock, R. (1991) Chromosome recombination and defective genome segrega­tion induced in CHO cells by the topoisomerase II inhibitor VM-26. Chromosoma 100, 97-102.
• 19. Ishida, R., Sato, M., Narita, T., Utsumi, K.R., Nishimoto, T., Morita, T., Nagata, H. & Andoh, T. (1994) Inhibition of DNA topoisomerase II by ICRF-193 induces polyploidization by uncou­pling chromosome dynamics from other cell cycle events. /. Cell Biol. 126,1341-1351.
• 20. Downes, C.S., Clarke, D.J., MuIIinger, A.M., Gimnez-Abian, J.R, Creighton, A.M. & Johnson, R.T. (1994) A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells. Nature (London) 372,467-470.
• 21. Kaufmann, S.H. (1991) Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. Cancer Res. 51,1129-1136.
• 22. D'Arpa, P. & Liu, L.F. (1989>Topoisomerase-tar- geting antitumor drugs. Biochim. Biophys. Acta 989,163-177.
• 23. Long, B.H., Musial, S.T. & Brattain, M.G. (1984) Comparison of cytotoxicity and DNA breakage activity of congeners of podophyllotoxin including VP16-213 and VM26: a quantitative structure-activity relationship. Biochemistry 23, 1183-1188.
• 24. Yang, L., Wold, M.S., Li, J.J., Kelly, T. & Liu, L.R (1987) Roles of DNA topoisomerases in simian virus 40 DNA replication in vitro. Proc. Natl. Acad. Sci. U.S.A. 84,950-954.
• 25. Richter, A., Strausfeld, U. & Knippers, R. (1987) Effects of VM26 (teniposide), a specific inhibitor of type II DNA topoisomerase, on SV40 DNA replication in vivo. Nucleic Acids Res. 15, 3455- -3467.
• 26. Dunaway, M. (1990) Inhibition of topoiso­merase II does not inhibit transcription of RNA polymerase I and II genes. Mol. Cell. Biol. 10, 2893-2900.
• 27. Chow, K. & Ross, W.E. (1987) Topoisomerase- -specific drug sensitivity in relation to cell cycle progression. Mol. Cell. Biol. 7,3119-3123.
• 28. Estey, E., Adlakha, R.C., Hittelman, W.N. & Zwelling, L.A. (1987) Cell cycle stagedependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity. Biochemistry 26,4338-4344.
• 29. D'Arpa, P., Beardmore, C. & Liu, L.F. (1990) Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res. 50,6919-6924.
• 30. Zhang, H., D'Arpa, P. & Liu, L.R (1990) A model for tumor cell killing by topoisomerase poisons. Cancer Cells 2,23-27.
• 31. Howard, M.T., Neece, S.H., Matson, S.W. & Kre- uzer, K.N. (1994) Disruption of a topoiso- merase-DNA cleavage complex by a DNA helicase. Proc. Natl. Acad. Sci. U.S.A. 91, 12031-12035.
• 32. Kaufmann, S.H. (1989) Induction of endo- nucleolytic DNA cleavage in human acute myelogenous leukemia cell lines by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res. 49, 5870- -5878.
• 33. Walker, P.R., Smith, C., Youdale, T., Leblanc, J., Whitfield, J.R & Sikorska, M. (1991) Topoiso- merase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res. 51, 1078-1085.
• 34. Razin, S.V., Hancock, R., Iarovaia, O.V., Westergaard, O., Gromova, I. & Georgiev, G.P. (1993) Structural-functional organization of chromosomal DNA domains. Cold Spring Harbor Symp. Quant. Biol. 58,25-35.
• 35. Iarovaia, O.V., Lagarkova, M.A. & Razin, S.V. (1995) The specificity of human lymphocyte nucleolar DNA long-range fragmentation by endogenous topoisomerase II and exogenous Bal 31 nuclease depends on cell proliferation status. Biochemistry 34,4133^1138.
• 36. Han, Y., Austin, M.J.R, Pommier, Y. & Povirk, L.F. (1993) Small deletion and insertion mutations induced by the topoisomerase II inhibitor teniposide in CHO cells and comparison with sites of drug-stimulated DNA cleavage in vitro, j. Mol Biol. 229,52-66.
• 37. Shibuya, M.L., Ueno, A.M., Vannais, D.B., Craven, PA. & Waldren, C.A. (1994) Megabase pair deletions in mutant mammalian cells following exposure to amsacrine, an inhibitor of DNA topoisomerase II. Cancer Res. 54, 1092- -1097.
• 38. Schmidt, V.K., Sorensen, B.S., S0rensen, H.V., Alsner, J. & Westergaard, O. (1994) Intramo­lecular and intermolecular DNA ligation medi- s ted by topoisomerase II. /. Mol. Biol. 241,18-25.
• 39. Ripley, L.S. (1994) Deletion and duplication induced in CHO cells by teniposide, a topo­isomerase II-targeting drug, can be explained by the processing of DNA nicks produced by the drug-topoisomerase II interaction. Mutation Res. 312, 67-78.
• 40. Bae,Y.S.,Chiba, M„ Ohira,M. &Ikeda, H. (1991) A shuttle vector for analysis of illegitimate recombination in mammalian cells: effects of DNA topoisomerase inhibitors on deletion frequency. Gene 101,285-289.
• 41. Pedersen-Bjergaard, J. & Philip, P. (1990) Balan­ced translocations involving chromosome bands llq23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting DNA-topoisomerase II. Blood 78,1147-1148.
• 42. Whitlock, J.A., Greer, J.P. & Lukens, J.N. (1991) Epipodophyllotoxin-related leukemia. Cancer 68,600-604.
• 43. Sugita, K., Furukawa, T., Tsuchida, M., Okawa, Y., Nakazawa, S., Akatsuka, J., Ohira, M. & Nis- himura, K. (1993) High frequency of etoposide- -related secondary leukemia in children with non-Hodgkin's lymphoma. Am. J. Pediatr. Hematol. Oncol. 15,99-104.
• 44. Haupt, R., Fears, T.R., Rosso, P., Colella, R., Loiacono, G., de Terlizzi, M., Mancini, A., Comelli, A., Indolfi, P. & Donfrancesco, A. (1994) Increased risk of secondary leukemia after single-agent treatment with etoposide for Langerhans cell histiocytosis. Pediatr. Hematol. Oncol. 11,499-507.
• 45. Felix, C.A., Hosler, M.R., Winick, N.J., Mas- terson, M., Wilson, A.E. & Lange, B.J. (1995) ALL-1 gene rearrangements in DNA topo­isomerase II inhibitor-related leukemia in children. Blood 85,3250-3256.
• 46. Legha, S.S., Ring, S., Raber, M„ Felder, T.B., Newman, R.A. & Krakoff, I.H. (1987) Phase I clinical investigation of benzisoquinolinedione. Cancer Treat. Rep. 71,1165-1169.
• 47. Saez, R„ Craig, J.B., Kuhn, J.G., Weiss, G.R., Koeller, J., Phillips, J., Havlin, K., Harman, G., Hardy, J„ Melink, T.J., et al. (1989) Phase I clinical investigation of amonafide. J. Clin. Oncol. 7, 1351-1358.
• 48. Kornek, G., Raderer, Mv Depisch, D., Haider,K., Fazeny, B„ Dittrich, C. & Scheithauer, W. (1994) Amonafide as first-line chemotherapy for metastatic breast cancer. Eur. J. Cancer 30A, 398- -400.
• 49. Canstanza, M.E., Berry, D., Henderson, I.C., Ratain, M.J., Wu, K., Shapiro, C., Duggan, D., Kalra, J., Berkowitz, I. & Lyss, A.P. (1995) Amo­nafide: an active agent in the treatment of pre­viously untreated advanced breast cancer — a cancer and leukemia Group B study (CALGB 8642). Clin. Cancer Res. 1,699-704.
• 50. Stein, C.A. (1993) Suramin: a novel antine­oplastic agent with multiple potential mecha­nisms of action. Cancer Res. 53,2239-2248.
• 51. Bojanowski, K., Lelievre, S., Markovits, J., Couprie, J., Jacquemin-Sablon, A. & Larsen, A.K. (1992) Suramin is an inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells. Proc. Natl. Acad. Sei. U.S.A. 89,3025-3029.
• 52. Larsen, A.K. (1993) Suramin: an anticancer drug with unique biological effects. Cancer Chemother. Pharmacol 32,96-98.
• 53. Hsieh, T & Brutlag, D. (1980) ATP-dependent DNA topoisomerase from D. melanogaster reversibly catenates duplex DNA rings. Cell 21, 115-125.
• 54. Eder, J.P., Teicher, B.A., Holden, S.A., Cathcart, K.N. & Schnipper, L.E. (1987) Novobiocin en­hances alkylating agent cytotoxicity and DNA interstrand crosslinks in a murine model. J. Clin. Invest. 79,1524-1528.
• 55. Eder, J.P., Teicher, B.A., Holden, S.A., Cathcart, K.N., Schnipper, L.E. & Freid, E. (1989) Effect of novobiocin on the antitumor activity and tumor cell bone marrow survivals of three alkylating agents. Cancer Res. 49,595-598.
• 56. Cotten, M., Bresnahan, D., Thompson, S., Sealy, L. & Chalkley, R. (1986) Novobiocin precipitates histones at concentrations normally used to inhibit eukaryotic type II topoisomerase. Nucleic Acids Res. 14,3671-3686.
• 57. Webb, M.L., Maguire, K.A. & Jacob, S.T. (1987) Novobiocin inhibits initiation of RNA poly­merase II-directed transcription of the mouse metallothionein-I gene independent of its effect on DNA topoisomerase II. Nucleic Acids Res. 15, 8547-8560.
• 58. Collins, A. (1990) Topoisomerase II can relax; novobiocin is a mitochondrial poison after all. Bio Essays 12,493-^194.
• 59. Kennedy, M.J., Armstrong, D.K., Huelskamp, A.M., Ohly, K., Clarke, B.V., Colvin, O.M., Gro- chow, L.B., Chen, T.L. & Davidson, N.E. (1995) Phase I and pharmacologic study of the alky­lating agent modulator novobiocin in combi­nation with high-dose chemotherapy for the treatment of metastatic breast cancer. /. Clin. Oncol. 13,1136-1143.
• 60. Beck, W.T., Danks, M.K., Wolverton, J.S., Chen, M., Granzen, B., Kim, R. & Suttle, D. (1994) Resistance of mammalian tumor cells to inhi­bitors of DNA topoisomerase II. Adv. Pharmacol. 29B, 145-169.
• 61. Pommier, Y., Leteurtre, F., Fesen, M.R., Fujimori, A., Bertrand, R., Solary, E., Kohlhagen, G. & Kohn, K.W. (1994) Cellular determinants of sen­sitivity and resistance to DNA topoisomerase inhibitors. Cancer Invest. 12,530-542.
• 62. Chen, A.Y. & Liu, L.F. (1994) Mechanisms of resistance to topoisomerase inhibitors. Cancer Treat. Rep. 73, 263-281.
• 63. Nitiss, J.L., Liu, Y., Harbury, P., Jannatipour, M., Wasserman, R. & Wang, J.C. (1992) Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II. Cancer Res. 52,4467-4472.
• 64. Eijdems, E.W., de Haas, M., Timmerman, A.J., Van der Schans, G.P., Kamst, E., de Nooij, J., Astaldi, R., Borst, P. & Baas, R (1995) Reduced topoisomerase II activity in multidrug resistant human non-small cell lung cancer lines. Br. J. Cancer 71,40^7.
• 65. Evans, C.D., Mirski, S.E., Danks, M. & Cole, S.P. (1994) Reduced levels of topoisomerase Ila and |3 in a multidrug-resistant lung cancer cell line. Cancer Chemother. Pharmacol. 34,242-248.
• 66. Endicott, J.A. & Ling, V. (1989) The biochemistry of P-glycoprotein-mediated multidrug resis­tance. Annu. Rev. Biochem. 58,137-161.
• 67. Brock, I., Hipfner, D.R., Nielsen, B.S., Jensen, P.B., Deeley, R.G., Cole, S.P.C. & Sehested, M. (1994) Sequential coexpression of the multidrug resistance genes MRP and mdrl and their pro­ducts in VP-16 (etoposide)-selected H69 small cell lung cancer cells. Cancer Res. 55,459-462.
• 68. Sikic, B.I. (1993) Modulation of multidrug resis­tance: at the threshold. J. Clin. Oncol. 11, 1629- -1635.
• 69. Eng, W.K., McCabe, F.L., Tan, K.B., Mattern, M.R., Hofmann, G.A., Woessner, R.D., Hertz- berg, R.P. & Johnson, R.K. (1990) Development of a stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content. Mol. Pharmacol. 38,471-480.
• 70. Friedman, H.S., Dolan, M.E., Kaufmann, S.H., Colvin, O.M., Griffith, O.W., Moschel, R.C., Schold, S.C., Bigner, D.D. & Ali-Osman, F. (1994) Elevated DNA polymerase alpha, DNA poly­merase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan. Cancer Res. 54,3487-3493.
• 71. Tannock, I.F. (1989) Principles of cell prolife­ration: cell kinetics; in Cancer Principles and Practice of Oncology (DeVita, V.T., Jr., Hellman, S. & Rosenberg, S.A., eds.) pp. 3-13, J.B. Lippi- ncott, Philadelphia.
• 72. Kaufmann, S.H., Karp, J.E., Jones, R.J., Miller, C.B., Schneider, E., Zwelling, L.A., Cowan, K., Wendel, K. & Burke, P.J. (1994) Topoisomerase II levels and drug sensitivity in adult acute myelo­genous leukemia. Blood 83,517-530.
• 73. Prosperi, E., Negri, C., Marchese, G. & Astaldi Riccoti, G.C.B. (1994) Expression of the 170 kDa isoforms of DNA topoisomerase II in resting and proliferating human lymphocytes. Cell Prolif. 27,257-267.
• 74. Chaudhary, P.M. & Roninson, I.B. (1993) Induc­tion of multidrug resistance in human cells by transient exposure to different chemothera- peutic drugs. J. Natl. Cancer Inst. 85,632-639.
• 75. Holden, J.A., Rolfson, D.H. & Wittwer, C.T. (1992) The distribution of immunoreactive topoisomerase II protein in human tissues and neoplasms. Oncol. Res. 4,157-166.
• 76. Holden, J.A., Rolfson, D.H. & Wittmer, C.T. (1990) Human DNA topoisomerase II: evalu­ation of enzyme activity in normal and neoplastic tissues. Biochemistry 29,2127-2134.
• 77. Potmesil, Mv Hsiang, Y.-H., Liu, L.F., Bank, B., Grossberg, H., Kirschenbaum, S., Forlenza, T.J., Penziner, A., Kanganis, D., Knowles, D., Tra- ganos, F. & Silber, R. (1988) Resistance of human leukemic and normal lymphocytes to drug- -induced DNA cleavage and low levels of DNA topoisomerase II. Cancer Res. 48,3537-3543.
• 78. Gekeler, V., Frese, G., Noller, A., Handgretinger, R., Wilisch, A., Schmidt, H., Muller, C.P., Dopfer, R., Klingebiel, T., et ai. (1992) Mdrl/P-glyco- protein, topoisomerase, and glutathione-S- - transferase pi gene expression in primary and relapsed state adult and childhood leukaemias. Br.}. Cancer 66,507-517.
• 79. Danks, M.K., Warmoth, M.R., Friche, E., Granzen, B., Bugg, B.Y., Harker, W.G., Zwelling, L.A., Futscher, B.W., Suttle, D.P. & Beck, W.T. (1993) Single-strand conformational poly­morphism analysis of the Mr 170,000 isozyme of DNA topoisomerase II in human tumor cells. Cancer Res. 53,1373-1379.
• 80. Stammler, G., Sauerbrey, A. & Volm, M. (1994) Determination of DNA topoisomerase II in newly diagnosed childhood acute lympho­blastic leukemia by immunocytochemistry and RT-PCR. Cancer Lett. 84,141-147.
• 81. Fossé, P., René, B., Saucier, J.-M., Hénichard, J.-P, Waring, M.J., Colson, P., Houssier, C. & Bailly, C. (1994) Stimulation of site-specific topoisomerase II-mediated DNA cleavage by a N-methylpyrrolecarboxamide-anilinoacridine conjugate: relation to DNA binding. Bioche­mistry 33,9865-9874.
• 82. Sprenson, B.S., Jensen, P.S., Andersen, A.H., Christiansen, K., Alsner,J., Thomsen, B. & Wes- tergaard, O. (1990) Stimulation of topo- iiomerase II mediated DNA cleavage at specific sequence elements by the 2-nitro- imidazole Ro 15-0216. Biochemistry 29,9507-9515.
• 83. Huff, A.C., Robinson, G., Evans, A.C., Selander, K.N., Wentland, M.P. & Rake, J.B. (1995) DNA sequence preference at sites cleaved by human DNA topoisomerase II in response to novel quinolone derivatives. Anticancer Drug Design 10,251-276.
• 84. De Isabella, P., Zunino, P. & Capranico, G. (1995) Base sequence determinants of amonafide stimulation of topoisomerase II DNA cleavage. Nucleic Acids Res. 23, 223-229.
• 85. Terada, T., Fujimoto, K., Nomura, M., Yama- shita, J., Wierzba, K., Yamazaki, R., Shibata, J., Sugimoto, Y., Yamada, Y. & Kobunai, T. (1993) Antitumor agents 3. Synthesis and biological activity of 4 j3~alkyl derivatives containing hydroxy, amino, and amido groups of 4'-0- -demethyl-4-desoxypodophyllotoxin as anti­tumor agents. }. Med. Chem. 36,1689-1699.
• 86. Leteurtre, F., Madalengoitia, J., Orr, A., Cuzi, T.J., Lehnert, T.J., Macdonald, T. & Pommier, Y. (1992) Rational design and molecular effects of a new topoisomerase II inhibitor, azatoxin. Cancer Res. 52,4478-4483.
• 87. Figgitt, D.P., Denny, W.A., Gamage, S.A. & Ralph, R.K. (1994) Structure-activity relation­ships of 9-anilinoacridines as inhibitors of human DNA topoisomerase II. Anticancer Drug Design 9,199-208.
• 88. Permana, P.A., Snapka, R.M., Shen, L.L., Chu, D.T.W., Clement, J.J. & Plattner, J.J. (1994) Qui- nobenoxazines: a class of novel quinolones and potent mammalian topoisomerase II catalytic inhibitors. Biochemistry 33,11333-11339.
• 89. Hsiang, W.H., Jiang, J.B. & Liu, L.F. (1989) Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs. Mol. Phar­macol. 36,371-376.
• 90. Leteurtre, F., Kohlhagen, G., Paull, K.D. & Pommier, Y. (1994) Topoisomerase II inhibition and cytotoxicity of the anthrapyrazole DuP937 and DuP941 (losoxantrone) in the NCI preclinical antitumor drug discovery screen. /. Natl. Cancer Inst. 86,1239-1244.
• 91. Corbett, A.H., Guerry P., Pflieger, P. & Osheroff, N. (1993) Apyrimido[l,6-al benzimidazole that enhances DNA cleavage by eukaryotic topo­isomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential. Antimicrob. Agents Chemother. 37,2599-2605.
• 92. Ritke, M.K., Roberts, D., Allan, W.P., Raymond, J., Bergoltz, V.V. & Yalowich, J.C. (1994) Altered stability of etoposide-induced topoisomerase II-DNA complexes in resistant human leukemia K562 cells. Br. J. Cancer 69, 687-697.
• 93. Campain, J.A., Gottesman, M.M. & Pastan, I. (1994) A novel mutant topoisomerase Ila present in VP16-resistant human melanoma cell lines has a deletion of alanine-429. Biochemistry 33,11327-11332.
• 94. Boege, F., Kjeldsen, E., Gieseler, F., Alsner, J. & Biersack, H. (1994) A drug-resistant variant of topoisomerase Ila in human HL-60 cells exhibits alterations in catalytic pH optimum, DNA binding, and subnuclear distribution. Eur. J. Biochem. 218,575-584.
• 95. Mirski, S.E.L. & Cole, S.P.C. (1995) Cytoplasmic localization of a mutant Mr 160,000 topoiso­merase Ila is associated with the loss of a puta­tive bipartite nuclear localization signal in a drug-resistant human lung cancer cell line. Cancer Res. 55,2129-2134.96. Harker, W.G., Slade, D.L., Parr, R.L., Feldhoff, P.W., Sullivan, D.M. & Holguin, M.H. (1995) Alterations in the topoisomerase II[3 gene, messenger RNA, and subcellular protein distribution as well as reduced expression of the DNA topoisomerase Hp enzyme in a mito- xantrone-resistant HL-60 human leukemia cell line. Cancer Res. 55,1707-1716.
• 97. Ritke, M.K., Allan, W.P., Fattman, C., Gunduz, N.N. & Yalowich, J.C. (1994) Reduced phospho­rylation of topoisomerase II in etoposide- -resistant human leukemia K562 cells. Mol. Pharmacol 46,58-66.
• 98. Takano, H., Kohno, K., Ono, N., Uchida, Y. & Kuwano, M. (1991) Increased phosphorylation of DNA topoisomerase II in etoposide-resistant mutants of human cancer KB cells. Cancer Res. 51,3951-3957.