Skip to main content
SpringerLink
Log in

Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma

  • Clinical–Patient Studies
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O6-benzylguanine (O6BG), sensitizes tumor cells to O6-alkylating agents. However, systemic administration of O6BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O6-alkylating drugs administered together with O6BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O6BG of a patient suffering from glioblastoma. O6BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide (Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O6BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O6BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O6-alkylating drugs) concomitant with O6BG without augmenting drug-induced systemic side effects.

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

Similar content being viewed by others

References

  1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588–593

    Article  PubMed  CAS  Google Scholar 

  2. 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 

  3. Gerson SL (2004) MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 4:296–307

    Article  PubMed  CAS  Google Scholar 

  4. Pegg AE (2000) Repair of O6-alkylguanine by alkyltransferases. Mutation Res 462:83–100

    Article  PubMed  CAS  Google Scholar 

  5. Kaina B, Fritz G, Mitra S, Coquerelle T (1991) Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis 12:1857–1867

    Article  PubMed  CAS  Google Scholar 

  6. Margison GP, Povey AC, Kaina B, Santibanez-Koref MF (2003) Variability and regulation of O6-alkylguanine-DNA alkyltransferase. Carcinogenesis 24:625–635

    Article  PubMed  CAS  Google Scholar 

  7. Kaina B, Christmann M (2002) DNA repair in resistance to alkylating anticancer drugs. Int J Clin Pharmacol Ther 40:354–367

    PubMed  CAS  Google Scholar 

  8. Preuss I, Eberhagen I, Haas S, Eibl RH, Kaufmann M, von Minckwitz G, Kaina B (1995) O6-methylguanine-DNA methyltransferase activity in breast and brain tumors. Int J Cancer 61:321–326

    PubMed  CAS  Google Scholar 

  9. Chen J, Zhang Y, Wang C, Sun Y, Fujimoto J, Ikenaga M (1992) O6-methylguanine DNA methyltransferase activity in human tumors. Carcinogenesis 13:1503–1507

    Article  PubMed  CAS  Google Scholar 

  10. Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos WP, Kaina B, Weller M (2006) MGMT and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem 96:766–776

    Article  PubMed  CAS  Google Scholar 

  11. Jaeckle KA, Eyre HJ, townsend JJ, Schulman S, Knodson HM, Belanich M, Yarosh DB, Bearman SI, Giroux DJ, Schold SC (1998) Correlation of tumor O6-methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a southwest oncology group study. J Clin Oncol 16:3310–3315

    PubMed  CAS  Google Scholar 

  12. Anda T, Shabani HK, Tsunoda K, Tokunaga Y, Kaminogo M, Shibata S, Hayashi T, Iseki M (2003) Relationship between expression of O6-methylguanine-DNA methyltransferase, glutathione-S-transferase pi in glioblastoma and the survival of the patients treated with nimustine hydrochloride: an immunohistochemical analysis. Neurol Res 25:241–248

    Article  PubMed  CAS  Google Scholar 

  13. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874

    Article  PubMed  CAS  Google Scholar 

  14. Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, Garcia-Lopez JL, Piquer J, Safont MJ, Balana C, Sanchez-Cespedes M, Garcia-Villanueva M, Arribas L, Esteller M (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 10:4933–4938

    Article  PubMed  CAS  Google Scholar 

  15. Dolan ME, Moschel RC, Pegg AE (1990) Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents. Proc Natl Acad Sci USA 87:5368–5372

    Article  PubMed  CAS  Google Scholar 

  16. Middleton MR, Lee SM, Arance A, Wood M, Thatcher N, Margison GP (2000) O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study. Int J Cancer 88:469–473

    Article  PubMed  CAS  Google Scholar 

  17. Rabik CA, Njoku MC, Dolan ME (2006) Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy. Cancer Treat Rev 32:261–276

    Article  PubMed  CAS  Google Scholar 

  18. Friedman HS, Pluda J, Quinn JA, Ewesuedo RB, Long L, Friedman AH, Cokgor I, Colvin OM, Haglund MM, Ashley DM, Rich JN, Sampson J, Pegg AE, Moschel RC, McLendon RE, Provenzale JM, Stewart ES, Tourt-Uhlig S, Garcia-Turner AM, Herndon JE 2nd, Bigner DD, Dolan ME (2000) Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 18:3522–3528

    PubMed  CAS  Google Scholar 

  19. Quinn JA, Pluda J, Dolan ME, Delaney S, Kaplan R, Rich JN, Friedman AH, Reardon DA, Sampson JH, Colvin OM, Haglund MM, Pegg AE, Moschel RC, McLendon RE, Provenzale JM, Gururangan S, Tourt-Uhlig S, Herndon JE II, Bigner DD, Friedman HS (2002) Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. J Clin Oncol 20:2277–2283

    Article  PubMed  CAS  Google Scholar 

  20. Quinn JA, Desjardins A, Weingart J, Brem H, Dolan ME, Delaney SM, Vredenburgh J, Rich J, Friedman AH, Reardon DA, Sampson JH, Pegg AE, Moschel RC, Birch R, McLendon RE, Provenzale JM, Gururangan S, Dancey JE, Maxwell J, Tourt-Uhlig S, Herndon JE II, Bigner DD, Friedman HS (2005) Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 23:7178–7187

    Article  PubMed  CAS  Google Scholar 

  21. Dickerman RD, Eisenberg MB (2005) Preassembled method for insertion of Ommaya reservoir. J Surg Oncol 89:36–38

    Article  PubMed  Google Scholar 

  22. Kaina B, Muhlhausen U, Piee-Staffa A, Christmann M, Garcia Boy R, Rosch F, Schirrmacher R (2004) Inhibition of O6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors: comparison with nonconjugated inhibitors and effect on fotemustine and temozolomide-induced cell death. J Pharmacol Exp Ther 311:585–593

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The trial was approved by the local ethic committee. For all steps of treatment written consent of the patient was obtained. We thank Georg Nagel for technical assistance.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Dorothee Koch

  2. Department of General Neurology, Johannes Gutenberg University, Mainz, Germany

    Thomas Hundsberger

  3. Department of Neuroradiology, Johannes Gutenberg University, Mainz, Germany

    Stephan Boor

  4. Department of Toxicology, Johannes Gutenberg University, Mainz, Germany

    Bernd Kaina

Authors
  1. Dorothee Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Hundsberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan Boor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernd Kaina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dorothee Koch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koch, D., Hundsberger, T., Boor, S. et al. Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma. J Neurooncol 82, 85–89 (2007). https://doi.org/10.1007/s11060-006-9244-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-006-9244-8

Keywords

Search

Navigation