Molecular and cellular response of the most extensively used rodent glioma models to radiation and/or cisplatin.
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.
Bencokova
Zuzana
Z
Inserm, U647, ID17, European Synchrotron Radiation Facility, Grenoble, 38043, France.
Pauron
Laurianne
L
Devic
Clément
C
Joubert
Aurélie
A
Gastaldo
Jérôme
J
Massart
Catherine
C
Balosso
Jacques
J
Foray
Nicolas
N
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000627:therapeutic use*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D005910:Glioma / Q000628:therapy*; D011878:Radiotherapy / Q000379:methods*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D002945:Cisplatin