| Abstract: |
Imatinib mesylate (STI571, Gleevec®) is a signal transduction inhibitor and novel anti-cancer agent. It selectively inhibits aberrantly activated tyrosine kinases in malignant cells, for example, bcr-abl in leukaemia, platelet-derived growth factor receptor and stem cell factor receptor (c-Kit) in solid cancers including malignant glioma. However, recently published clinical studies with imatinib monotherapy in patients with malignant glioma demonstrated only very modest anti-tumour activity. The aim of this study was to investigate the biological activity of imatinib, its cellular mechanisms of action and its synergism with other chemotherapeutic agents in human malignant glioma cells in culture. Expression of PDGF/R and c-Kit was analyzed by RT-PCR. Proliferation was measured by MTT assays and drug synergy was assessed by the Chou-Talalay method. Cell cycle and apoptosis were analyzed by flow cytometry and migration by monolayer migration assays. Multi-immunoblot was performed on imatinib-treated and control malignant glioma cells. Results indicate that imatinib is more effective in inhibiting cell colony formation and migration rather than proliferation. Imatinib treatment caused cell cycle arrest of glioma cells in G0-G1 or G2/M, with significant elevation of a few cyclin-dependent kinases. Furthermore, imatinib acted synergistically with chemotherapy agents, such as the DNA alkylating agent, temozolomide, and riboneucleotide reductase inhibitors, for example, hydroxyurea at varied effective dose levels. In conclusion, imatinib exerts varied biological effects on malignant glioma cells in culture. Synergistic interaction of imatinib with chemotherapy agents may be related to cell cycle control mechanisms and could be potentially important in a clinical setting. © 2009 Nordic Pharmacological Society. |
| Keywords: |
signal transduction; platelet derived growth factor; controlled study; protein expression; human cell; hydroxyurea; drug potentiation; gemcitabine; temozolomide; flow cytometry; glioma; antineoplastic agent; cell proliferation; cell cycle; imatinib; stem cell factor receptor; drug inhibition; proto-oncogene proteins c-kit; reverse transcription polymerase chain reaction; apoptosis; cell growth; antineoplastic combined chemotherapy protocols; cell line; drug effect; cell line, tumor; platelet derived growth factor receptor; pyrimidines; protein tyrosine kinase inhibitor; drug synergism; gene expression regulation, neoplastic; biological activity; drug mechanism; reverse transcriptase polymerase chain reaction; glioma cell; glioblastoma; immunoblotting; cell migration; cell movement; cell cycle arrest; cell cycle g2 phase; cell cycle m phase; flavopiridol; piperazines; cyclin dependent kinase; cell cycle regulation; technique; cell cycle g1 phase; concentration response; cell cycle g0 phase; receptors, platelet-derived growth factor; 3 (4,5 dimethyl 2 thiazolyl) 2,5 diphenyltetrazolium bromide; 3,4 dihydroxybenzohydroxamic acid; chou talalay method; growth inhibition
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