Flavopiridol inhibits the Growth of GL261 Gliomas In Vivo: Implications for Malignant Glioma Therapy

Abstract

The mechanism of action of many chemotherapeutic agents targets the cell cycle. Recently, we demonstrated cytotoxic and other anti-tumor effects of flavopiridol, the first synthetic cyclin dependent kinase (CDK) inhibitor to enter clinical trials, on the murine GL261 glioma cell line in vitro (Newcomb et al., Cell Cycle 2003; 2:243). Given that flavopiridol has demonstrated anti-tumor activity in several human xenograft models, we wanted to evaluate it for anti-glioma activity in vivo in our established subcutaneous and intracranial GL261 experimental tumor models. In particular, the intracranial animal model recapitulates many of the histopathological and biological features of human high-grade glioma including both necrosis with pseudopalisading and invasion of the brain adjacent to tumor. Here we tested the activity of flavopiridol against tumors formed by GL261 cells, first as subcutaneous implants, and then in the intracranial model. We demonstrate efficacy of flavopiridol as a single modality treatment in delaying tumor growth in both animal models. We hypothesize that flavopiridol treatment induced tumor growth delay by two possible mechanisms involving growth arrest combined with recruitment of tumor cells to S-phase. Based on our findings, flavopiridol should be considered as a treatment approach for patients with high-grade glioma. © L a n d e s B i o s c i e n c e 2 0 0 4. N o t f o r d i s t r i b u t i o n .

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

“…36,37 In addition to its ability to kill cells in S phase, flavopiridol also can recruit cells into the S phase when it is delivered 48 or 72 h apart. 11,32 Our results demonstrate that the schedules chosen for radiation and flavopiridol treatments produced a highly significant delay in tumor growth. Since noncycling cells are relatively radio-resistant, the enhanced radiosensitizing effects of flavopiridol observed in this study of repeated doses of both radiation and flavopiridol treatments can be hypothesized to be due, at least in part, to its ability to affect tumor repopulation.…”

“…We and others have shown that flavopiridol is an S-phase specific drug. 11,[33][34][35] We elected to give fractionated radiation in a protracted schedule of 5 fractions of 5 Gy delivered over ten days in order to test our hypothesis that flavopiridol would selectively kill proliferating cells in S phase, by overcoming repopulation of tumor cells between fractionated radiation treatments. 36,37 In addition to its ability to kill cells in S phase, flavopiridol also can recruit cells into the S phase when it is delivered 48 or 72 h apart.…”

“…This dose and schedule of flavopiridol for three weeks delayed growth of GL261 flank tumors, as we described previously. 11 The tumors were measured twice weekly and the mean tumor volume calculated as described above. Animals were sacrificed when the tumor volume reached > 2500 mm 3 .…”

“…8,9 Preclinical in vitro and in vivo results supported further investigations using the GL261 cells with the novel cyclin dependent kinase inhibitor flavopiridol. 10,11 Flavopiridol, a semi-synthetic flavone, has pleiotropic effects as an anti-cancer agent, mechanisms that may be associated with its known ability to affect gene transcription. [12][13][14][15] Our work demonstrated that, as a monotherapy, flavopiridol was effective in delaying GL261 tumors growing in the flank as well as in the brain 11 and this was correlated with an anti-angiogenic effect on the tumor vasculature.…”

“…10,11 Flavopiridol, a semi-synthetic flavone, has pleiotropic effects as an anti-cancer agent, mechanisms that may be associated with its known ability to affect gene transcription. [12][13][14][15] Our work demonstrated that, as a monotherapy, flavopiridol was effective in delaying GL261 tumors growing in the flank as well as in the brain 11 and this was correlated with an anti-angiogenic effect on the tumor vasculature. 16 Flavopiridol has been investigated for its potential to enhance the effect of radiotherapy in several animal models including human colon, gastric, and lung xenografts and murine ovarian, breast and lymphoma syngeneic tumors.…”