Journal of Neuro-Oncology

, Volume 86, Issue 1, pp 13–21

Molecular and cellular response of the most extensively used rodent glioma models to radiation and/or cisplatin

  • Zuzana Bencokova
  • Laurianne Pauron
  • Clément Devic
  • Aurélie Joubert
  • Jérôme Gastaldo
  • Catherine Massart
  • Jacques Balosso
  • Nicolas Foray
Lab. Investigation-Human/Animal Tissue


Purpose Anti-glioma strategies are generally based on trials involving rodent models whose choice remains based on proliferative capacity and availability. Recently, our group obtained the most protracted survival of rats bearing F98 gliomas by combining synchrotron X-rays and intracerebral cisplatin injection (Biston et al., Cancer Res, 64:2317–2323, 2004). The response to such treatment was suggested to be dependent on BRCA1, a tumour suppressor known to be involved in the response to radiation and cisplatin. In order to verify the impact of BRCA1 functionality upon success of anti-glioma trials, radiobiological features and BRCA1-dependent stress signalling were investigated in the most extensively used rodent glioma models. Methods Cell death pathways, cell cycle arrests, DNA repair and stress signalling were evaluated in response to radiation and cisplatin in C6, 9L and F98 models. Results Rodent glioma models showed a large spectrum of cellular radiation response. Surprisingly, BRCA1 was found to be functionally impaired in C6 and F98 favouring genomic instability, tumour heterogeneity and tolerance of unrepaired DNA damage. Significance Our findings strengthened the importance of the choice of the glioma model on genetic and radiobiological bases, inasmuch as all these rat glioma models are induced by nitrosourea-mediated mutagenesis that may favour specific gene mutations. Particularly, BRCA1 status may condition the response to anti-glioma treatments. Furthermore, since BRCA1 acts as a tumour suppressor in a number of malignancies, our findings raise also the question of the implication of BRCA1 in brain tumours formation.


Glioma BRCA1 DSB repair Cisplatin 


  1. 1.
    Behin A, Hoang-Xuan K, Carpentier AF, Delattre JY (2003) Primary brain tumours in adults. Lancet 361:323–331PubMedCrossRefGoogle Scholar
  2. 2.
    Lesniak MS, Brem H (2004) Targeted therapy for brain tumours. Nat Rev Drug Discov 3:499–508PubMedCrossRefGoogle Scholar
  3. 3.
    Bredel M (2001) Anticancer drug resistance in primary human brain tumors. Brain Res Brain Res Rev 35:161–204PubMedCrossRefGoogle Scholar
  4. 4.
    Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506PubMedCrossRefGoogle Scholar
  5. 5.
    Marot D, Opolon P, Brailly-Tabard S, Elie N, Randrianarison V, Connault E, Foray N, Feunteun J, Perricaudet M (2006) The tumor suppressor activity induced by adenovirus-mediated BRCA1 overexpression is not restricted to breast cancers. Gene Ther 13:235–244PubMedCrossRefGoogle Scholar
  6. 6.
    Holland EC (2001) Brain tumor animal models: importance and progress. Curr Opin Oncol 13:143–147PubMedCrossRefGoogle Scholar
  7. 7.
    Schlegel J, Piontek G, Kersting M, Schuermann M, Kappler R, Scherthan H, Weghorst C, Buzard G, Mennel H (1999) The p16/Cdkn2a/Ink4a gene is frequently deleted in nitrosourea-induced rat glial tumors. Pathobiology 67:202–206PubMedCrossRefGoogle Scholar
  8. 8.
    Asai A, Miyagi Y, Sugiyama A, Gamanuma M, Hong SH, Takamoto S, Nomura K, Matsutani M, Takakura K, Kuchino Y (1994) Negative effects of wild-type p53 and s-Myc on cellular growth and tumorigenicity of glioma cells. Implication of the tumor suppressor genes for gene therapy. J Neurooncol 19:259–268PubMedCrossRefGoogle Scholar
  9. 9.
    Benda P, Lightbody J, Sato G, Levine L, Sweet W (1968) Differentiated rat glial cell strain in tissue culture. Science 161:370–371PubMedCrossRefGoogle Scholar
  10. 10.
    Senatus PB, Li Y, Mandigo C, Nichols G, Moise G, Mao Y, Brown MD, Anderson RC, Parsa AT, Brandt-Rauf PW, Bruce JN, Fine RL (2006) Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide. Mol Cancer Ther 5:20–28PubMedCrossRefGoogle Scholar
  11. 11.
    Ko L, Koestner A, Wechsler W (1980) Morphological characterization of nitrosourea-induced glioma cell lines and clones. Acta Neuropathol (Berl) 51:23–31CrossRefGoogle Scholar
  12. 12.
    Zhu Y, Parada LF (2002) The molecular and genetic basis of neurological tumours. Nat Rev Cancer 2:616–626PubMedCrossRefGoogle Scholar
  13. 13.
    Corde S, Balosso J, Elleaume H, Renier M, Joubert A, Biston MC, Adam JF, Charvet AM, Brochard T, Le Bas JF, Esteve F, Foray N (2003) Synchrotron photoactivation of cisplatin elicits an extra number of DNA breaks that stimulate RAD51-mediated repair pathways. Cancer Res 63:3221–3227PubMedGoogle Scholar
  14. 14.
    Biston MC, Joubert A, Adam JF, Elleaume H, Bohic S, Charvet AM, Esteve F, Foray N, Balosso J (2004) Cure of Fisher rats bearing radioresistant F98 glioma treated with cis-platinum and irradiated with monochromatic synchrotron X-rays. Cancer Res 64:2317–2323PubMedCrossRefGoogle Scholar
  15. 15.
    Foray N, Priestley A, Alsbeih G, Badie C, Capulas EP, Arlett CF, Malaise EP (1997) Hypersensitivity of ataxia telangiectasia fibroblasts to ionizing radiation is associated with a repair deficiency of DNA double-strand breaks. Int J Radiat Biol 72:271–283PubMedCrossRefGoogle Scholar
  16. 16.
    Foray N, Marot D, Gabriel A, Randrianarison V, Carr AM, Perricaudet M, Ashworth A, Jeggo P (2003) A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. Embo J 22:2860–2871PubMedCrossRefGoogle Scholar
  17. 17.
    Barth RF (1998) Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 36:91–102PubMedCrossRefGoogle Scholar
  18. 18.
    Joubert A, Foray N (2006) Repair of radiation-induced DNA double-strand breaks in human cells: history, progress and controversies (Chapter 10). In: Landseer BR (ed) New Research on DNA Repair. Nova Science, Hauppauge NYGoogle Scholar
  19. 19.
    Foray N, Randrianarison V, Marot D, Perricaudet M, Lenoir G, Feunteun J (1999) Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2. Oncogene 18:7334–7342PubMedCrossRefGoogle Scholar
  20. 20.
    Lee SA, Dritschilo A, Jung M (2001) Role of ATM in oxidative stress-mediated c-Jun phosphorylation in response to ionizing radiation and CdCl2. J Biol Chem 276:11783–11790PubMedCrossRefGoogle Scholar
  21. 21.
    Rothkamm K, Lobrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci USA 100:5057–5062PubMedCrossRefGoogle Scholar
  22. 22.
    Udayakumar D, Bladen CL, Hudson FZ, Dynan WS (2003) Distinct pathways of nonhomologous end joining that are differentially regulated by DNA-dependent protein kinase-mediated phosphorylation. J Biol Chem 278:41631–41635PubMedCrossRefGoogle Scholar
  23. 23.
    Chavaudra N, Bourhis J, Foray N (2004) Quantified relationship between cellular radiosensitivity, DNA repair defects and chromatin relaxation: a study of 19 human tumour cell lines from different origin. Radiother Oncol 73:373–382PubMedCrossRefGoogle Scholar
  24. 24.
    Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM (1997) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88:265–275PubMedCrossRefGoogle Scholar
  25. 25.
    Zan Y, Haag JD, Chen KS, Shepel LA, Wigington D, Wang YR, Hu R, Lopez-Guajardo CC, Brose HL, Porter KI, Leonard RA, Hitt AA, Schommer SL, Elegbede AF, Gould MN (2003) Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nat Biotechnol 21:645–651PubMedCrossRefGoogle Scholar
  26. 26.
    Ueki K, Nishikawa R, Nakazato Y, Hirose T, Hirato J, Funada N, Fujimaki T, Hojo S, Kubo O, Ide T, Usui M, Ochiai C, Ito S, Takahashi H, Mukasa A, Asai A, Kirino T (2002) Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin Cancer Res 8:196–201PubMedGoogle Scholar
  27. 27.
    Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD, Sikic BI (2005) High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res 65:4088–4096PubMedCrossRefGoogle Scholar
  28. 28.
    Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM (1999) BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol Cell Biol 19:4843–4854PubMedGoogle Scholar
  29. 29.
    Deans AJ, Khanna KK, McNees CJ, Mercurio C, Heierhorst J, McArthur GA (2006) Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers. Cancer Res 66:8219–8226PubMedCrossRefGoogle Scholar
  30. 30.
    Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukada Y (1983) Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint radiation therapy oncology group and eastern cooperative oncology group study. Cancer 52:997–1007PubMedCrossRefGoogle Scholar
  31. 31.
    Wolff JE, Trilling T, Molenkamp G, Egeler RM, Jurgens H (1999) Chemosensitivity of glioma cells in vitro: a meta analysis. J Cancer Res Clin Oncol 125:481–486PubMedCrossRefGoogle Scholar
  32. 32.
    Jenkin RD, Boesel C, Ertel I, Evans A, Hittle R, Ortega J, Sposto R, Wara W, Wilson C, Anderson J et al (1987) Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the childrens cancer study group. J Neurosurg 66:227–233PubMedCrossRefGoogle Scholar
  33. 33.
    Sheleg SV, Korotkevich EA, Zhavrid EA, Muravskaya GV, Smeyanovich AF, Shanko YG, Yurkshtovich TL, Bychkovsky PB, Belyaev SA (2002) Local chemotherapy with cisplatin-depot for glioblastoma multiforme. J Neurooncol 60:53–59PubMedCrossRefGoogle Scholar
  34. 34.
    Fehlauer F, Muench M, Rades D, Stalpers LJ, Leenstra S, van der Valk P, Slotman B, Smid EJ, Sminia P (2005) Effects of irradiation and cisplatin on human glioma spheroids: inhibition of cell proliferation and cell migration. J Cancer Res Clin Oncol 131:723–732PubMedCrossRefGoogle Scholar
  35. 35.
    Taghian A, Ramsay J, Allalunis-Turner J, Budach W, Gioioso D, Pardo F, Okunieff P, Bleehen N, Urtasun R, Suit H (1993) Intrinsic radiation sensitivity may not be the major determinant of the poor clinical outcome of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 25:243–249PubMedGoogle Scholar
  36. 36.
    Taghian A, Suit H, Pardo F, Gioioso D, Tomkinson K, DuBois W, Gerweck L (1992) In vitro intrinsic radiation sensitivity of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 23:55–62PubMedGoogle Scholar
  37. 37.
    Foray N, Marot D, Randrianarison V, Venezia ND, Picard D, Perricaudet M, Favaudon V, Jeggo P (2002) Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Mol Cell Biol 22:4020–4032PubMedCrossRefGoogle Scholar
  38. 38.
    Rosen EM, Fan S, Isaacs C (2005) BRCA1 in hormonal carcinogenesis: basic and clinical research. Endocr Relat Cancer 12:533–548PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Zuzana Bencokova
    • 1
  • Laurianne Pauron
    • 1
  • Clément Devic
    • 1
  • Aurélie Joubert
    • 1
    • 2
  • Jérôme Gastaldo
    • 1
  • Catherine Massart
    • 1
  • Jacques Balosso
    • 1
    • 3
  • Nicolas Foray
    • 1
  1. 1.Inserm, U647, ID17European Synchrotron Radiation FacilityGrenobleFrance
  2. 2.Institut de Radioprotection et de Sûreté NucléaireFontenay-aux-RosesFrance
  3. 3.Département de Cancérologie et d’HématologieCHU MichallonGrenobleFrance

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