Cytotoxic Effects of Temozolomide and Radiation are Additive- and Schedule-Dependent
| Autor: | Elliot M. Ruff, Nadia Lovegrove, Christine Martindale, Susan C Short, Anthony J. Chalmers |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
G2 Phase
Cancer Research Pathology medicine.medical_specialty DNA Repair DNA repair Morpholines medicine.medical_treatment Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Radiation Tolerance Drug Administration Schedule O(6)-Methylguanine-DNA Methyltransferase Radiation sensitivity Caffeine Cell Line Tumor Temozolomide medicine Humans Radiology Nuclear Medicine and imaging CHEK1 Phosphorylation Antineoplastic Agents Alkylating Checkpoint Kinase 2 Tumor Stem Cell Assay Radiation business.industry Tumor Suppressor Proteins Cell cycle Combined Modality Therapy Neoplasm Proteins DNA-Binding Proteins Dacarbazine Radiation therapy Oncology Pyrones Checkpoint Kinase 1 Cancer research Radiosensitizing Agent Glioblastoma business Protein Kinases medicine.drug |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 75:1511-1519 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2009.07.1703 |
| Popis: | Purpose: Despite aggressive therapy comprising radical radiation and temozolomide (TMZ) chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor, particularly if tumors express O{sup 6}-methylguanine-DNA-methyltransferase (MGMT). The interactions between radiation and TMZ remain unclear and have important implications for scheduling and for developing strategies to improve outcomes. Methods and Materials: Factors determining the effects of combination therapy on clonogenic survival, cell-cycle checkpoint signaling and DNA repair were investigated in four human glioma cell lines (T98G, U373-MG, UVW, U87-MG). Results: Combining TMZ and radiation yielded additive cytotoxicity, but only when TMZ was delivered 72 h before radiation. Radiosensitization was not observed. TMZ induced G2/M cell-cycle arrest at 48-72 h, coincident with phosphorylation of Chk1 and Chk2. Additive G2/M arrest and Chk1/Chk2 phosphorylation was only observed when TMZ preceded radiation by 72 h. The ataxia-telangiectasia mutated (ATM) inhibitor KU-55933 increased radiation sensitivity and delayed repair of radiation-induced DNA breaks, but did not influence TMZ effects. The multiple kinase inhibitor caffeine enhanced the cytotoxicity of chemoradiation and exacerbated DNA damage. Conclusions: TMZ is not a radiosensitizing agent but yields additive cytotoxicity in combination with radiation. Our data indicate that TMZ treatment should commence at least 3 days before radiation to achievemore » maximum benefit. Activation of G2/M checkpoint signaling by TMZ and radiation has a cytoprotective effect that can be overcome by dual inhibition of ATM and ATR. More specific inhibition of checkpoint signaling will be required to increase treatment efficacy without exacerbating toxicity.« less |
| Databáze: | OpenAIRE |
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