Radiation sensitivity of GL261 murine glioma model and enhanced radiation response by flavopiridol.
Response of a solid tumor to radiation treatment depends, in part, on the intrinsic radiosensitivity of tumor cells, the proliferation rate of tumor cells between radiation treatments and the hypoxic state of the tumor cells. A successful radiosensitizing agent would target S-phase cells and hypoxia. Recently, we demonstrated the anti-tumor effects of flavopiridol in the GL261 murine glioma model might involve 1) recruitment of tumor cells to S-phase (Newcomb et al Cell Cycle 2004; 3:230-234) and 2) an anti-angiogenic effect on the tumor vasculature by downregulation of hypoxia-inducible factor -1alpha (HIF-1alpha) (Newcomb et al Neuro-Oncology 2005; 7:225-235). Given that flavopiridol has demonstrated radiosensitizing activity in several murine tumor models, we tested whether it would enhance the response of GL261 tumors to radiation. In the present study, we evaluated the intrinsic radiation sensitivity of the GL261 glioma model using the tumor control/cure dose of radiation assay (TCD(50)). We found that a single dose of 65 Gy (CI 57.1-73.1) was required to cure 50% of the tumors locally. Using the tumor growth delay assay, fractionated radiation (5 fractions of 5 Gy over 10 days) combined with flavopiridol (5 mg/kg) given three times weekly for 3 cycles produced a significant growth delay. Our results indicate that the GL261 murine glioma model mimics the radioresistance encountered in human gliomas, and thus should prove useful in identifying promising new investigational radiosensitizers for use in the treatment of glioma patients.
Newcomb
Elizabeth W
EW
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York, USA.
Lymberis
Stella C
SC
Lukyanov
Yevgeniy
Y
Shao
Yongzhao
Y
Schnee
Tona
T
Devitt
Marylou
M
Rosenstein
Barry S
BS
Zagzag
David
D
Formenti
Silvia C
SC
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D035002:Lower Extremity / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib