Skip to main content
SpringerLink
Log in

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

  • Commentary
  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Duchrow M, Gerdes J, Schluter C. The proliferation associated Ki-67 protein: definition in molecular terms. Cell Prolif 27:235–242, 1994.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  8. Wang JC. DNA topoisomerases. Annul Rev Biochem 65:635–692, 1996.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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. Adachi Y, Luke M, Laemmli UK. Chromosome assembly in vitro: topoisomerase II is required for condensation. Cell 64:137–148, 1991.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  14. Austin CA, Marsh KL. Eukaryotic DNA topoisomerase β. BioEssays 20:215–226, 1998.

    Article  PubMed  CAS  Google Scholar 

  15. Gilmour DS, Pflugfelder G, Warng JC, Lis JT. Topoisomerase I interacts with transcribed regions in drosophila cells. Cell 44:401–407, 1986.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  18. Heck MMS, Earnshaw WC. Topoisomerase II: a specific marker for cell proliferation. J Cell Biol 103:2569–2581, 1986.

    Article  PubMed  CAS  Google Scholar 

  19. Holden JA. Human deoxyribonucleic acid topoisomerases: molecular targets of anticancer drugs. Ann Clin Lab Sci 27:402–412, 1997.

    PubMed  CAS  Google Scholar 

  20. Osheroff N, Corbett AH, Robinson MJ. Mechanism of action of topoisomerase II targeted antineoplastic drugs. Adv Pharmacol 29B:105–125, 1994.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  44. Pelosi G, Zamboni G. Proliferation markers and their uses in the study of endocrine tumors. Endocr. Pathol. 7:103–119, 1996.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  48. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967, 1993.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Surgical Pathology Department of Pathology, University of Utah Health Sciences Center, 84132, Salt Lake City, UT

    Joseph A. Holden MD

Authors
  1. Joseph A. Holden MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holden, J.A. DNA Topoisomerase II-alpha as a marker of cell proliferation in endocrine and other neoplasms. Endocr Pathol 10, 97–102 (1999). https://doi.org/10.1007/BF02739821

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02739821

Key Words

Search

Navigation