Radiation Sensitivity of GL261 Murine Glioma Model and Enhanced Radiation Response by Flavopiridol

Abstract

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; 3:230-4) and (2) an anti-angiogenic effect on the tumor vasculature by downregulation of hypoxia-inducible factor-1α (HIF-1α) (Newcomb et al., Neuro-Oncology 2005; 7:225-35). 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 three 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.

The Combination of Ionizing Radiation and Peripheral Vaccination Produces Long-term Survival of Mice Bearing Established Invasive GL261 Gliomas

“…GL261 gliomas are relatively radioresistant tumors (TCD 50 = 65 Gy; ref. 8). Consequently, the modest dose of radiation used in our experiments is unlikely to have resulted in sufficient cell death to explain the clinical response observed (Fig.…”

Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo

“…Individually, lapatinib, CDK inhibitors and obatoclax all have been shown to promote radiosensitization by mechanisms as diverse as inhibition of NFκB; suppression of cyto-protective protein expression and the generation of ROS and autophagy. [41][42][43] In addition to causing DNA damage, one well recognized route of ionizing Figure 2A-D (See opposite page). Lapatinib and obatoclax interact to kill mammary carcinoma cells.…”

Interspecies Comparative Genomic Hybridization (I-CGH): A New Twist to Study Animal Tumor Models

“…Glioma radiation models very often involve small rodents to study tumor cell radiosensitivity in combination with different radiosensitizing compounds. 21 But mice represent quite distant species from human, and some studies require more adequate animal models, for example, using primates for the analyses who are physiologically much closer to human. M. mulatta has been used widely in biomedical and pharmaceutical research, but its genome has been significantly less studied than that of other mammals which represents a limitation for studying molecular mechanisms of disease in the non-human primate.…”