Endocrine Pathology

, Volume 10, Issue 2, pp 97–102

DNA Topoisomerase II-alpha as a marker of cell proliferation in endocrine and other neoplasms

  • Joseph A. Holden


DNA topoisomerases are enzymes that are able to link and unlink DNA strands. They are classified as type I or type II topoisomerase if they catalyze transient single-strand (topo I) or double-strand (topo II) DNA breaks. Topo II-alpha has been used as a proliferation marker and it can also serve as a molecular target for a variety of anticancer drugs that are used clinically.

Topo II-alpha expression is similar to MIB1 immunoreactivity in breast, ovarian, cervix, gastric, endometrial, adrenocortical, and hematological malignancies. In a study of adrenocortical tumors with metastases topo II was significantly higher than in tumors without metastases.

Studies of topo II-alpha expression may provide information about the biological behavior of specific tumors and may also provide insights into the role that this enzyme plays in the response of human cancers to topo II-targeted anticancer drugs.

Key Words

Cell proliferation topoisomerase II-alpha adrenocortical tumors MIB1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Duchrow M, Gerdes J, Schluter C. The proliferation associated Ki-67 protein: definition in molecular terms. Cell Prolif 27:235–242, 1994.PubMedGoogle Scholar
  2. 2.
    Cattoretti G, Becker MHG, Key G, Duchrow M, Schluter C, Galle J, Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB1 and MIB3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168:357–363, 1992.PubMedCrossRefGoogle Scholar
  3. 3.
    Deshmukh P, Ramsey L, Garewal HS. Ki-67 labeling index is a more reliable measure of solid tumor proliferative activity than tritiated thymidine labeling. Am Clin Pathol 94: 192–195, 1990.Google Scholar
  4. 4.
    Onda K, Davis RL, Shibuyo M, Wilson CB, Hoshino T. Correlation between the bromodeoxyuridine labeling index and the MIB-1 and Ki-67 proliferating cell indices in cerebral gliomas. Cancer 74: 1921–1926, 1994.PubMedCrossRefGoogle Scholar
  5. 5.
    Dervan PA, Gilmartin LG, Loftus B, Carney DN. Breast carcinoma kinetics: argyrophilic nucleolar organizer region counts correlate with Ki67 scores. Am J Clin Pathol 92:401–407 1989.PubMedGoogle Scholar
  6. 6.
    Burford-Mason AP, MacKay AJ, Cummins M, Dardick I. Detection of proliferating cell nuclear antigen in paraffin-embedded specimens is dependent on preembedding tissue handling and fixation. Am J Clin Pathol 118:1007–1013, 1994.Google Scholar
  7. 7.
    Linden MD, El-Naggar AK, Nathanson SD, Jacobson G, Zarbo RJ. Correlation between flow cytometric and immunohistochemical proliferation measurements of human tumors. Mod Pathol 9:682–689, 1996.PubMedGoogle Scholar
  8. 8.
    Wang JC. DNA topoisomerases. Annul Rev Biochem 65:635–692, 1996.CrossRefGoogle Scholar
  9. 9.
    Pflugfelder MT, Liu LF, Liu AA, Tewey KM, Wang-Pheng J, Knutsen T, et al. Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21–22. Proc Natl Acad Sci USA 81:2616–2620, 1984.CrossRefGoogle Scholar
  10. 10.
    Tan KB, Dorman TE, Falls KM, Chung TDY, Mirabelli CK, Crooke ST, et al. Topoisomerase II-alpha and topoisomerase II-beta genes—characterization and mapping to human chromosome-17 and chromosome-3 respectively. Cancer Res 52:2 31–234, 1992.Google Scholar
  11. 11.
    Adachi Y, Luke M, Laemmli UK. Chromosome assembly in vitro: topoisomerase II is required for condensation. Cell 64:137–148, 1991.PubMedCrossRefGoogle Scholar
  12. 12.
    DiNardo S, Voelkel K, Sternglanz R. DNA topoisomerase II mutant of Saccharomyces cerevisiae: topoisomerase II is required for segregation of daughter molecules at the terminati on of DNA replication. Proc Natl Acad Sci USA 81:2616–2620, 1984.PubMedCrossRefGoogle Scholar
  13. 13.
    Holm C, Stearns T, Botstein D. DNA topoisomerase II must act at mitosis to prevent nondisjunction and chromosome breakage. Mol Cell Biol 9:159–168, 1989.PubMedGoogle Scholar
  14. 14.
    Austin CA, Marsh KL. Eukaryotic DNA topoisomerase β. BioEssays 20:215–226, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Gilmour DS, Pflugfelder G, Warng JC, Lis JT. Topoisomerase I interacts with transcribed regions in drosophila cells. Cell 44:401–407, 1986.PubMedCrossRefGoogle Scholar
  16. 16.
    Heck MMS, Hittelman WN, Earnshaw WC. Differential expression of DNA topoisomerases i and II during the eukaryotic cell cycle. Proc Natl Acad Sci USA 85:1086–1090, 1988.PubMedCrossRefGoogle Scholar
  17. 17.
    Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH. Proliferation-and cell cycle-dependent differences in the expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ 2:209–214, 1991.PubMedGoogle Scholar
  18. 18.
    Heck MMS, Earnshaw WC. Topoisomerase II: a specific marker for cell proliferation. J Cell Biol 103:2569–2581, 1986.PubMedCrossRefGoogle Scholar
  19. 19.
    Holden JA. Human deoxyribonucleic acid topoisomerases: molecular targets of anticancer drugs. Ann Clin Lab Sci 27:402–412, 1997.PubMedGoogle Scholar
  20. 20.
    Osheroff N, Corbett AH, Robinson MJ. Mechanism of action of topoisomerase II targeted antineoplastic drugs. Adv Pharmacol 29B:105–125, 1994.PubMedCrossRefGoogle Scholar
  21. 21.
    Burden DA, Kingma PS, Froelich-Ammon SJ, Bjornsti MA, Patchan MW, Thompson RB, et al. Topoisomerase II etoposide interactions direct the formation of drug-induced enzyme-DNA cleavage complexes. J Biol Chem 271:29,238–29,244, 1996.Google Scholar
  22. 22.
    Hsiang Y, Liu LF. Evidence for the reversibility of cellular DNA lesion induced by mammalian topoisomerase II poisons. J Biol Chem 264:9713–9715, 1989.PubMedGoogle Scholar
  23. 23.
    Caldecott K, Banks G, Jeggo P. DNA double-strand break repair pathways and cellular tolerance to inhibitors of topoisomerase II. Cancer Res 50:5778–5783, 1990.PubMedGoogle Scholar
  24. 24.
    Catapano CV, Carbone GM, Pisani F, Qiu J, Fernandes DJ. Arrest of replication fork progression at sites of topoisomerase II-mediated DNA cleavage in human leukemia CEM cells incubated with VM-26. Biochemistry 36: 5730–5748, 1997.CrossRefGoogle Scholar
  25. 25.
    Nitiss JL, Wang JC. Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol. Pharm 50:1095–1102, 1996.Google Scholar
  26. 26.
    Nitiss JL, Ya-Xia L, Harbury P, Jannatipour M, Wasserman R, Wang JC. Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II. Cancer Res 52:4467–4472, 1992.PubMedGoogle Scholar
  27. 27.
    Sullivan DM, Latham MD, Ross WD. Proliferation-dependent topoisomerase II content as a determinant of antineoplastic drug action in human, mouse, and chinese hamster ovary cells. Cancer Res 47:3973–3979, 1987.PubMedGoogle Scholar
  28. 28.
    Davies SM, Robson CN, Davies S, Hickson ID. Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to interaclating agents and epipodophyllotoxins. J Biol Chem 263:17,724–17,729, 1988.Google Scholar
  29. 29.
    Asano T, An T, Mayes J, Zwelling LA, Kleinerman S. Transfection of human topoisomerase II-alpha into etoposide-resistant cells: transient increase in sensitivity followed by down regulation of the endogenous gene. Biochem J 319:307–313, 1996.PubMedGoogle Scholar
  30. 30.
    Holden JA, Snow GW, Perkins SL, Kjeldsberg CR. Immunohistochemical staining for DNA topoisomerase II in frozen and formalin-fixed paraffin embedded human tissues. Mod Pathol 7:829–834, 1994.PubMedGoogle Scholar
  31. 31.
    Kellner U, Heidebrecht H, Rudoloph P, Biersack H, Buck F, Dakowski T, et al. Detection of human topoisomerase II-alpha in cell lines and tissues: characterization of five novel monoclonal antibodies. J Histochem Cytochem. 45:251–263, 1997.PubMedGoogle Scholar
  32. 32.
    Lynch BJ, Guinee DG, Holden JA. Human DNA topoisomerase II-alpha: a new marker of cell proliferation in invasive breast cancer. Hum Pathol 28:1180–1188, 1997.PubMedCrossRefGoogle Scholar
  33. 33.
    Martinchick JC, Rahn MP, Jolles CJ, Holden JA. Human DNA topoisomerase II-alpha: immunohistochemical staining for enzyme protein in tumors of ovarian origin. Int. J Oncol 10:1229–1234, 1997.Google Scholar
  34. 34.
    Gibbons D, Fogt F, Kasznica J, Holden JA, Nikulasson S. Comparison of topoisomerase II-alpha and MIB1 expression in uterine cervical squamous lesions. Mod Pathol 10:409–413, 1997.PubMedGoogle Scholar
  35. 35.
    Yabuki N, Sasano H, Kato K, Ohara S, Toyota T, Nagura H, et al. Immunohistochemical study of DNA topoisomerase II in human gastric disorders. Amer J Pathol 149:997–1007, 1996.Google Scholar
  36. 36.
    Ito K, Sasano H, Yabuki N, Matsunaga G, Sato S, Kikuchi A, et al. Immunohistochemical study of Ki-67 and DNA topoisomerase II in human endometrium. Mod Pathol 10:289–294, 1997.PubMedGoogle Scholar
  37. 37.
    Holden JA, Perkins SL, Snow GW, Kjeldsberg CR. Immunohistochemical staining for DNA topoisomerase II in non-Hodgkin’s lymphomas. Am J Clin Pathol 104:54–59, 1995.PubMedGoogle Scholar
  38. 38.
    Rudolph P, Kellner U, Chassevent A, Collin F, Bonichon F, Parwaresch R, et al. Prognostic relevance of a novel proliferation marker, Ki-S 11, for soft tissue sarcoma. Am J Pathol 150:1997–2007, 1997.PubMedGoogle Scholar
  39. 39.
    Bauman ME, Holden JA, Brown KA, Harker WG, Perkins SL. Differential immunohistochemical staining for DNA topoisomerase II-alpha and beta in human tissues and for DNA topoisomerase II-beta in non-Hodgkin’s lymphomas. Mod Pathol 10:168–175, 1997.PubMedGoogle Scholar
  40. 40.
    Perret AG, Mosnier JF, Buono JP, Berthelot P, Chipponi J, Balique JG, et al. The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors. Amer. J. Clin. Pathol. 109:286–293, 1998.Google Scholar
  41. 41.
    Katoh R, Bray CE, Suzuke K, Komiyama A, Hemmi A, Kawaoi A, et al. Growth activity in hyperplastic and neoplastic human thyroid determined by an immunohistochemical staining procedure using monoclonal antibody MIB-1. Hum Pathol 26:139–146, 1995.PubMedCrossRefGoogle Scholar
  42. 42.
    Lloyd RV, Carney JA, Ferreiro JA, Jin L, Thompson GB, van Heerden JA, Grant CS, Wollan PC. Immunohistochemical analysis of the cell cycle associated antigens Ki-67 and retinoblastoma protein in parathyroid carcinomas and adenomas. Endocr Pathol. 6:279–287, 1995.PubMedGoogle Scholar
  43. 43.
    Vargas MP, Vargas HI, Kleiner DE, Merino MJ. Adrenocortical neoplasms: role of prognostic markers MIB-1, p53, and RB. Amer. J. Surg. Pathol. 21:556–562, 1997.CrossRefGoogle Scholar
  44. 44.
    Pelosi G, Zamboni G. Proliferation markers and their uses in the study of endocrine tumors. Endocr. Pathol. 7:103–119, 1996.PubMedGoogle Scholar
  45. 45.
    Iino K, Sasano H, Yabuki N, Yutaka O, Kikuchi A, Yoshimi T, Oki Y. DNA topoisomerase II-alpha and Ki-67 in human adrenocortical neoplasms: a possible marker of differential between adenomas and carcinomas. Mod Pathol 10:901–907, 1997.PubMedGoogle Scholar
  46. 46.
    Guinee DG, Holden JA, Benfield JB, Woodward ML, Przygodzki RM, Fishback NF, et al. Comparison of DNA topoisomerase II-alpha expression in small cell and non small cell carcinoma of the lung—In search of a mechanism of chemotherapeutic response. Cancer, 78:729–735, 1996.PubMedCrossRefGoogle Scholar
  47. 47.
    Brown MS, Holden JA, Rahn MP, Perkins SL. Immunohistochemical staining for DNA topoisomerase II-alpha in Hodgkin’s disease. Am J Clin Pathol 109:39–44, 1998.PubMedGoogle Scholar
  48. 48.
    Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967, 1993.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1999

Authors and Affiliations

  • Joseph A. Holden
    • 1
  1. 1.Division of Surgical Pathology Department of PathologyUniversity of Utah Health Sciences CenterSalt Lake City

Personalised recommendations