Journal of Neuro-Oncology

, Volume 84, Issue 1, pp 31–37 | Cite as

The combined effects of multiple chemotherapeutic agents for malignant glioma cells

  • Takao Nakagawa
  • Toshihiko Kubota
  • Kazunori Ido
  • Takahiro Sakuma
  • Ken Matsuda
Laboratory Investigation


The prognosis of malignant gliomas remains poor, despite the progress of surgery and radiotherapy. Chemotherapy has been shown to prolong an overall survival, but the benefits are still small. To overcome this situation, the optimal regimen of antineoplastic agents is required. In the present study, we investigated the effect of the association of five chemotherapeutic drugs, including ACNU, CBDCA, CDDP, VCR, and VP-16, on cell survival of U87, YKG1, A172, and U251 human glioma cell lines, using median-effect analysis. A synergistic effect was obtained by treatment involving the association of VP-16 with ACNU or CDDP among the combinations of two drugs, and the association of ACNU, CBDCA, and VP-16 in the combination of three drugs. This preclinical screening using median-effect analysis supports the design of clinical trials by indicating more effective combinations of antineoplastic agents for malignant gliomas.


Glioma Chemotherapy In vitro Median effect analysis 



Nimustine hydrochloride






Glyceraldehyde-3-phosphate dehydrogenase


Glutathione S-transferase π


Multidrug resistance 1


Multidrug resistance-associated protein 1


Multidrug resistance-associated protein 3


[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium, inner salt]


O6-methylguanine-DNA methyltransferase








  1. 1.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018PubMedCrossRefGoogle Scholar
  2. 2.
    Janss AJ, Cnaan A, Zhao H et al (1998) Synergistic cytotoxicity of topoisomerase I inhibitors with alkylating agents and etoposide in human brain tumor cell lines. Anticancer Drugs 9:641–652PubMedCrossRefGoogle Scholar
  3. 3.
    Shingu T, Yamada K, Hara N (2003) Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells. Cancer Res 63:4044–4047PubMedGoogle Scholar
  4. 4.
    Balzarotti M, Ciusani E, Calatozzolo C et al (2004) Effect of association of temozolomide with other chemotherapic agents on cell growth inhibition in glioma cell lines. Oncol Res 14:325–330PubMedGoogle Scholar
  5. 5.
    Chou TC, Talalay P (1981) Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem 115:207–216PubMedCrossRefGoogle Scholar
  6. 6.
    Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55PubMedCrossRefGoogle Scholar
  7. 7.
    McDaid HM, Johnston PG (1999) Synergistic interaction between paclitaxel and 8-chloro-adenosine 3′, 5′-monophosphate in human ovarian carcinoma cell lines. Clin Cancer Res 5:215–220PubMedGoogle Scholar
  8. 8.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  9. 9.
    Bredel M, Zentner J (2002) Brain-tumour drug resistance: The bare essentials. Lancet Oncol 3:397–406PubMedCrossRefGoogle Scholar
  10. 10.
    Kimmel DW, Shapiro JR, Shapiro WR (1987) In vitro drug sensitivity testing in human gliomas. J Neurosurg 66:161–171PubMedCrossRefGoogle Scholar
  11. 11.
    Barrie M, Couprie C, Dufour H et al (2005) Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. Ann Oncol 16:1177–1184PubMedCrossRefGoogle Scholar
  12. 12.
    Korones DN, Smith A, Foreman N et al (2006) Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas. Pediatr Blood Cancer 47:37–41PubMedCrossRefGoogle Scholar
  13. 13.
    Herrlinger U, Rieger J, Koch D et al (2006) Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J Clin Oncol 24:4412–4417PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Takao Nakagawa
    • 1
  • Toshihiko Kubota
    • 1
  • Kazunori Ido
    • 1
  • Takahiro Sakuma
    • 1
  • Ken Matsuda
    • 1
  1. 1.Department of NeurosurgeryUniversity of FukuiFukuiJapan

Personalised recommendations