Skip to main content
SpringerLink
Log in

Enhanced expression of DNA topoisomerase II genes in human medulloblastoma and its possible association with etoposide sensitivity

  • Lab. Inverstigation-human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Medulloblastoma (MB) is the most common malignant neuroepithelial tumor of childhood. The DNA topoisomerase II (Topo II) inhibitor etoposide has been widely used for the treatment of MBs; however, it remains unknown whether MB cells are more sensitive to etoposide than other malignant neuroepithelial tumor cells. In this study, we tested the chemosensitivities of malignant neuroepithelial tumors (26 glioblastomas, 9 anaplastic astrocytomas, and 5 MBs) to etoposide and vincristine using the succinate dehydrogenase inhibition test and found that MB cells are more sensitive to etoposide and more resistant to vincristine than other tumor cells. We performed quantitative reverse-transcription polymerase chain reaction to evaluate the expression of genes related to etoposide sensitivity, and found co-overexpression of DNA topoisomerase II (Topo II) α and β mRNA in MBs. In addition, the levels of Topo IIα and β mRNA in these tumors correlated with etoposide sensitivity. Immunohistochemical studies using surgical samples of these tumors demonstrated that the percentages of Topo IIα immunopositive cells (Topo IIα labeling index) correlated with those of Ki-67 immunopositive cells (MIB-1 labeling index); however, neither the Topo IIα nor the MIB-1 labeling index correlated with the levels of Topo IIα mRNA or etoposide sensitivity. Based on these observations, Topo IIα and β mRNA expression, but not the Topo IIα labeling index, might be a useful marker for sensitivity to etoposide in human malignant neuroepithelial tumors.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225, discussion 226–229

    PubMed  Google Scholar 

  2. Rood BR, Macdonald TJ, Packer RJ (2004) Current treatment of medulloblastoma: recent advances and future challenges. Semin Oncol 31:666–675

    Article  PubMed  Google Scholar 

  3. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    Article  PubMed  CAS  Google Scholar 

  4. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  5. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR et al (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725–1731

    Article  PubMed  CAS  Google Scholar 

  6. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986

    Article  PubMed  CAS  Google Scholar 

  7. Castello MA, Clerico A, Deb G, Dominici C, Fidani P, Donfrancesco A (1990) High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors. Am J Pediatr Hematol Oncol 12:297–300

    PubMed  CAS  Google Scholar 

  8. Gentet JC, Doz F, Bouffet E, Plantaz D, Roche H, Tron P, Kalifa C, Mazingue F, Sariban E, Chastagner P et al (1994) Carboplatin and VP 16 in medulloblastoma: a phase II Study of the French Society of Pediatric Oncology (SFOP). Med Pediatr Oncol 23:422–427

    Article  PubMed  CAS  Google Scholar 

  9. Heideman RL, Kovnar EH, Kellie SJ, Douglass EC, Gajjar AJ, Walter AW, Langston JA, Jenkins JJ, Li Y, Greenwald C et al (1995) Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors. J Clin Oncol 13:2247–2254

    PubMed  CAS  Google Scholar 

  10. Busca A, Miniero R, Besenzon L, Cordero di Montezemolo L, Cenni M, Fagioli F, Sandri A, Vassallo E, Ricardi U, Madon E (1997) Etoposide-containing regimens with autologous bone marrow transplantation in children with malignant brain tumors. Childs Nerv Syst 13:572–577

    Article  PubMed  CAS  Google Scholar 

  11. Sawamura Y, Ikeda J, Ishii N, Kato T, Tada M, Abe H, Shirato H (1996) Combined irradiation and chemotherapy using ifosfamide, cisplatin, and etoposide for children with medulloblastoma/posterior fossa primitive neuroectodermal tumor—results of a pilot study. Neurol Med Chir (Tokyo) 36:632–638

    Article  CAS  Google Scholar 

  12. Hainsworth JD, Greco FA (1995) Etoposide: twenty years later. Ann Oncol 6:325–341

    PubMed  CAS  Google Scholar 

  13. Taniguchi K, Wakabayashi T, Yoshida T, Mizuno M, Yoshikawa K, Kikuchi A, Nakashima N, Yoshida J (1999) Immunohistochemical staining of DNA topoisomerase IIalpha in human gliomas. J Neurosurg 91:477–482

    PubMed  CAS  Google Scholar 

  14. Dingemans AM, Witlox MA, Stallaert RA, van der Valk P, Postmus PE, Giaccone G (1999) Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer. Clin Cancer Res 5:2048–2058

    PubMed  CAS  Google Scholar 

  15. Matsumoto Y, Takano H, Fojo T (1997) Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype. Cancer Res 57:5086–5092

    PubMed  CAS  Google Scholar 

  16. Mirski SE, Evans CD, Almquist KC, Slovak ML, Cole SP (1993) Altered topoisomerase II alpha in a drug-resistant small cell lung cancer cell line selected in VP-16. Cancer Res 53:4866–4873

    PubMed  CAS  Google Scholar 

  17. Taki T, Ohnishi T, Arita N, Hiraga S, Hayakawa T (1998) In vivo etoposide-resistant C6 glioma cell line: significance of altered DNA topoisomerase II activity in multi-drug resistance. J Neurooncol 36:41–53

    Article  PubMed  CAS  Google Scholar 

  18. Matsumoto T, Tani E, Kaba K, Kochi N, Shindo H, Yamamoto Y, Sakamoto H, Furuyama J (1990) Amplification and expression of a multidrug resistance gene in human glioma cell lines. J Neurosurg 72:96–101

    Article  PubMed  CAS  Google Scholar 

  19. Matsumoto Y, Takano H, Nagao S, Fojo T (2001) Altered topoisomerase IIalpha and multidrug resistance-associated protein levels during drug selection: adaptations to increasing drug pressure. Jpn J Cancer Res 92:968–974

    PubMed  CAS  Google Scholar 

  20. Matsumoto Y, Tamiya T, Nagao S (2005) Resistance to topoisomerase II inhibitors in human glioma cell lines overexpressing multidrug resistant associated protein (MRP) 2. J Med Invest 52:41–48

    Article  PubMed  Google Scholar 

  21. Maehara Y, Anai H, Kusumoto H, Sugimachi K (1987) Poorly differentiated human gastric carcinoma is more sensitive to antitumor drugs than is well differentiated carcinoma. Eur J Surg Oncol 13:203–206

    PubMed  CAS  Google Scholar 

  22. Kawahara N, Tanaka T, Yokomizo A, Nanri H, Ono M, Wada M, Kohno K, Takenaka K, Sugimachi K, Kuwano M (1996) Enhanced coexpression of thioredoxin and high mobility group protein 1 genes in human hepatocellular carcinoma and the possible association with decreased sensitivity to cisplatin. Cancer Res 56:5330–5333

    PubMed  CAS  Google Scholar 

  23. Holden JA, Townsend JJ (1999) DNA topoisomerase II-alpha as a proliferation marker in astrocytic neoplasms of the central nervous system: correlation with MIB1 expression and patient survival. Mod Pathol 12:1094–1100

    PubMed  CAS  Google Scholar 

  24. Ashley DM, Meier L, Kerby T, Zalduondo FM, Friedman HS, Gajjar A, Kun L, Duffner PK, Smith S, Longee D (1996) Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol 14:1922–1927

    PubMed  CAS  Google Scholar 

  25. Chamberlain MC, Kormanik PA (1997) Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol 17:230–234

    Article  PubMed  CAS  Google Scholar 

  26. Needle MN, Molloy PT, Geyer JR, Herman-Liu A, Belasco JB, Goldwein JW, Sutton L, Phillips PC (1997) Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol 29:28–32

    Article  PubMed  CAS  Google Scholar 

  27. Oyharcabal-Bourden V, Kalifa C, Gentet JC, Frappaz D, Edan C, Chastagner P, Sariban E, Pagnier A, Babin A, Pichon F, Neuenschwander S, Vinchon M, Bours D, Mosseri V, Le Gales C, Ruchoux M, Carrie C, Doz F (2005) Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23:4726–4734

    Article  PubMed  CAS  Google Scholar 

  28. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479

    Article  PubMed  CAS  Google Scholar 

  29. Oloumi A, MacPhail SH, Johnston PJ, Banath JP, Olive PL (2000) Changes in subcellular distribution of topoisomerase IIa correlate with etoposide resistance in multicell spheroids and xenograft tumors. Cancer Res 60:5457–5753

    Google Scholar 

  30. McLean TW (2003) Medulloblastomas and central nervous system primitive neuroectodermal tumors. Curr Treat Options Oncol 4:499–508

    Article  PubMed  Google Scholar 

  31. Bredel C, Lassmann S, Pollack IF, Knoth R, Hamilton RL, Volk B, Werner M, Bredel M (2005) DNA topoisomerase IIalpha and Her-2/neu gene dosages in pediatric malignant gliomas. Int J Oncol 26:1187–1192

    PubMed  CAS  Google Scholar 

  32. Mendrzyk F, Korshunov A, Toedt G, Schwarz F, Korn B, Joos S, Hochhaus A, Schoch C, Lichter P, Radlwimmer B (2006) Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats. Genes Chromosomes Cancer 45:401–410

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Tomomi Yamada (Department of Medical Information Science, Kyushu University Hospital) for her invaluable assistance in statistical analysis, Saori Uchida for her excellent technical assistance, and Mikiko Hidaka and Emiko Uchiyama (Department of Neurosurgery, Kyushu University Graduate School of Medical Sciences) for assistance with manuscript preparation.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Toshio Uesaka, Tadahisa Shono, Daisuke Kuga, Kenichi Matsumoto, Masahiro Mizoguchi & Tomio Sasaki

  2. Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Satoshi O. Suzuki & Toru Iwaki

  3. Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan

    Hiroaki Niiro & Kyoko Miyamoto

  4. Department of Neurosurgery, Kyushu Rosai Hospital, Kitakyushu, Japan

    Masaru Ohta

Authors
  1. Toshio Uesaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadahisa Shono
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daisuke Kuga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoshi O. Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroaki Niiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kyoko Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenichi Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahiro Mizoguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masaru Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toru Iwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tomio Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tadahisa Shono.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Uesaka, T., Shono, T., Kuga, D. et al. Enhanced expression of DNA topoisomerase II genes in human medulloblastoma and its possible association with etoposide sensitivity. J Neurooncol 84, 119–129 (2007). https://doi.org/10.1007/s11060-007-9360-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-007-9360-0

Keywords

Search

Navigation