Skip to main content

Advertisement

SpringerLink
Log in

The effects of temozolomide delivered by prolonged intracerebral microinfusion against the rat brainstem GBM allograft model

  • Original Paper
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Objective

Diffuse intrinsic brainstem gliomas are considered to be inoperable. We report our initial experience of temozolomide (TMZ) administration into brainstem by intracerebral (i.c.) microinfusion using a rat brainstem glioblastoma allograft model.

Methods

Forty-eight Fischer 344 female rats were used. In a feasibility study, various doses of i.c.-TMZ (1–10 mg) were administered into the brainstem using AlzetTM pumps in order to evaluate survival rates and neurotoxicity. For tumor implantation, rats received an injection of 105 9 L gliosarcoma cells. For local therapy, 5 days after inoculation, a total amount of 1 mg of TMZ or saline was administered into the brainstem at 1 μl/h over 7 days (n = 8/group). For systemic therapy, rats were treated with an orally administered maximum daily dose of 50 mg/kg TMZ for 5 consecutive days. Survival time and neurological deficit were recorded as outcome parameters.

Results

In the neurotoxicity study, low dose TMZ (1 mg) was feasible to be administered into brainstem over 7 days without neurological deficit. Using high dose TMZ (5–10 mg), marked neurotoxic effect was observed. In the brainstem tumor study, survival was significantly prolonged in low dose i.c.-TMZ group compared to control rats (median survival 23.5 versus 29.5 days; p < 0.01). Systemic therapy with maximal oral-TMZ dose resulted in longer survival time compared to low dose i.c.-TMZ group (median survival 33.5 versus 29.5 days; p < 0.01).

Conclusions

i.c.-TMZ is feasible and effective against rat brainstem glioblastoma allograft. However, we could not show superior potential of i.c.-TMZ compared to oral-TMZ administration. Modification of TMZ infusion with systemic therapy warrants future investigations.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bernier-Chastagner V, Grill J, Doz F, Bracard S, Gentet JC, Marie-Cardine A, Luporsi E, Margueritte G, Lejars O, Laithier V, Mechinaud F, Millot F, Kalifa C, Chastagner P (2005) Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Pediatric Oncology Phase II Study. Cancer 104:2792–2797

    Article  PubMed  CAS  Google Scholar 

  2. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery to macromolecules in the brain. Proc Natl Acad Sci USA 91:2076–2080

    Article  PubMed  CAS  Google Scholar 

  3. Brem S, Tyler B, Li K, Pradilla G, Legnani F, Caplan J, Brem H (2007) Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model. Cancer Chemother Pharmacol 60:643–650

    Article  PubMed  CAS  Google Scholar 

  4. Carson CB Sr, Wu Q, Tyler B, Sukay L, Raychaudhuri R, DiMeco F, Clatterbuck RE, Olivi A, Guarnieri M (2002) New approach to tumor therapy for inoperable areas of the brain: chronic intraparenchymal drug delivery. J Neurooncol 60:151–158

    Article  PubMed  Google Scholar 

  5. Degen JW, Walbridge S, Vortmeyer AO, Oldfield EH, Lonser RR (2003) Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a maligmant glioma model in rats. J Neurosurg 99:893–898

    Article  PubMed  CAS  Google Scholar 

  6. Epstein F, Wisoff JH (1998) Intrinsic brainstem tumors in childhood, surgical indications. J Neurosurg 6:309–317

    Google Scholar 

  7. Frazier JM, Lee J, Thomale UW, Noggle JC, Cohen JK, Jallo GI (2009) Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies. A review J Neurosurg Pediatrics 3:259–269

    Article  Google Scholar 

  8. Freeman CR, Krischer J, Sanford RA, Burger PC, Cohen M, Norris D (1988) Hyper fractionated radiotherapy in brain stem tumors: results of a Pediatric Oncology Group study. Int J Radiat Oncol Bio Phys 15:311–318

    Article  CAS  Google Scholar 

  9. Freeman CR, Krischer JP, Sanford RA, Burger PC, Cohen M, Norris D (1993) Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 30:197–206

    Google Scholar 

  10. Guarnieri M, Carson BS Sr (2004) Chronic local therapy for brainstem tumors. Neurosurgery 54:1025–1026

    Article  PubMed  Google Scholar 

  11. Guarnieri M, Carson BS Sr, Jallo GI (2008) Catheters for chronic administration of drugs into brain tissue. Methods Mol Biol 437:109–117

    Article  PubMed  CAS  Google Scholar 

  12. Heimberger AB, Archer GE, McLendon RE, Hulette C, Friedman AH, Friedman HS, Bigner DD, Sampson JH (2000) Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats. Clin Cancer Res 6:4148–4153

    PubMed  CAS  Google Scholar 

  13. Jallo GI, Becker M, Liu YJ, Carson BS Sr, Guarnieri M (2006) Local infusion therapy in the monkey brainstem: technical considerations. Surg Technol Int 15:311–316

    PubMed  Google Scholar 

  14. Jallo GI, Volkov A, Wong C, Carson BS Sr, Penno MB (2006) A novel brainstem tumor model: fuctional and histopathological characterization. Childs Nerv Syst 22:1–2

    Article  PubMed  Google Scholar 

  15. Lee J, Jallo GI, Guarnieri M, Carson BS Sr, Penno MB (2005) A novel brainstem tumor model: guide screw technology with functional, radiological, and histopathological characterization. Neurosurg Focus 18:E11

    Article  PubMed  Google Scholar 

  16. Kato T, Natsume A, Toda H, wamizu H, Sugita T, Hachisu R, Watanabe R, Yuki K, Motomura K, Bankiewicz K, Wakabayashi T (2010) Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxicity of temozolomide in GBM-initiating cells. Gene Therapy 17:1363–1371

    Article  PubMed  CAS  Google Scholar 

  17. Lieberman DM, Laske DW, Morrison PF, Bankievicz KS, Oldfield EH (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:1021–1029

    Article  PubMed  CAS  Google Scholar 

  18. Murad GJ, Walbridge S, Morrison PF, Garmestani K, Degen JW, Brechbiel MW, Oldfield EH, Lonser RR (2006) Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to pseudomonas exotoxin. Clin Cancer Res 12:3145–3151

    Article  PubMed  CAS  Google Scholar 

  19. Natsume A, Ishii D, Wakabayashi T, Tsuno T, Hatano H, Mizuno M, Yoshida J (2005) INF-β down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. Cancer Res 65:7573–7579

    PubMed  CAS  Google Scholar 

  20. Occhiogrosso G, Edgar MA, Sandberg DI, Souweidane MM (2003) Prolonged convection-enhanced delivery into the rat brainstem. Neurosurgery 52:388–394

    Article  PubMed  Google Scholar 

  21. 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 2nd, 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 

  22. Sandberg DI, Edgar MA, Souweidane MM (2002) Convection-enhanced delivery into the rat brainstem. J Neurosurg 96:885–891

    Article  PubMed  Google Scholar 

  23. Souweidane MM, Occhiogrosso G, Mark EB, Edgar MA, Dunkel IJ (2004) Interstitial infusion of carmustine in the rat brain stem with systemic administration of O6-benzylguanine. J Neurooncol 67:319–326

    Article  PubMed  Google Scholar 

  24. Strege RJ, Liu YJ, Kiely A, Johnson RM, Gillis EM, Storm P, Carson BS, Jallo GI, Guarnieri M (2004) Toxicity and cerebrospinal fluid levels of carboplatin chronically infused into the brainstem of a primate. J Neurooncol 67:327–334

    Article  PubMed  CAS  Google Scholar 

  25. Thomale UW, Tyler B, Renard VM, Dorfman B, Guarnieri M, Haberl HE, Jallo GI (2009) Local chemotherapy in the rat brainstem with multiple catheters: a feasibility study. Childs Nerv Syst 25:21–28

    Article  PubMed  CAS  Google Scholar 

  26. Thomale UW, Tyler B, Renard V, Dorfman B, Guarnieri M, Haberl HE, Jallo GI (2009) Neurological grading, survival, MR imaging, and histological evaluation in the rat brainstem glioma model. Childs Nerv Syst 25:433–441

    Article  PubMed  CAS  Google Scholar 

  27. Vredenburgh JJ, Desjardins A, Herndon JE II, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizmab plus irrinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729

    Article  PubMed  CAS  Google Scholar 

  28. Wagner S, Warmuth-Metz M, Emser A, Gnekow AK, Sträter R, Rutkowski S, Jorch N, Schmid HJ, Berthold F, Graf N, Kortmann RD, Pietsch T, Sorensen N, Peters O, Wolff JE (2006) Treatment options in childhood pontine gliomas. J Neurooncol 79:281–287

    Article  PubMed  Google Scholar 

  29. Walker DA, Punt JA, Sokai M (1999) Clinical management of brainstem glioma. Arch Dis Child 80:558–567

    Article  PubMed  CAS  Google Scholar 

  30. Wu Q, Guarnieri M, Tyler B, Clatterbuck RE, Liu Y, Carson BS (2004) Section on tumors: Young Investigator Award: local release of carboplatin via an Alzet mini-osmotic pump prolongs survival in a rat brainstem tumor model. Clin Neurosurg 51:332–339

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Junichi Yoshimura, I-Mei Siu & George I. Jallo

  2. Department of Neurosurgery, Brain Research Institute, University of Niigata, Chuo-ku Asahimachi 1-757, Niigata City, Niigata, Japan, 951-8585

    Junichi Yoshimura

  3. Pediatric Neurosurgery, Charité–Virchow Medical Center, Augstenburger Plaz 1, 13353, Berlin, Germany

    Ulrich-W Thomale

Authors
  1. Junichi Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I-Mei Siu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ulrich-W Thomale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George I. Jallo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junichi Yoshimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshimura, J., Siu, IM., Thomale, UW. et al. The effects of temozolomide delivered by prolonged intracerebral microinfusion against the rat brainstem GBM allograft model. Childs Nerv Syst 28, 707–713 (2012). https://doi.org/10.1007/s00381-012-1732-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-012-1732-x

Keywords

Search

Navigation