Flavopiridol inhibits the growth of GL261 gliomas in vivo: implications for malignant glioma therapy.
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.
Newcomb
Elizabeth W
EW
Department of Pathology, New York University Cancer Institute; New York University School of Medicine, New York, New York 10016, USA. newcoe01@med.nyu.edu
Tamasdan
Cristina
C
Entzminger
Yolanda
Y
Arena
Elizabeth
E
Schnee
Tona
T
Kim
Mimi
M
Crisan
Diana
D
Lukyanov
Yevgeniy
Y
Miller
Douglas C
DC
Zagzag
David
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division / Q000502:physiology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib