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Chalmers, Anthony J, Ruff, Elliot M, Martindale, Christine, Lovegrove, Nadia and Short, Susan C (2009) Cytotoxic effects of temozolomide and radiation are additive- and schedule-dependent. International Journal of Radiation: Oncology - Biology - Physics, 75 (5). pp. 1511-1519. ISSN 0360-3016
Full text not available from this repository.Abstract
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 O6-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 achieve 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.
| Item Type: | Article |
|---|---|
| Keywords: | Glioblastoma multiforme; Temozolomide; Radiation therapy; G2/M checkpoint; Chemoradiation |
| Schools and Departments: | School of Life Sciences > Sussex Centre for Genome Damage and Stability |
| Subjects: | R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens |
| Depositing User: | Lisa Costick |
| Date Deposited: | 01 Sep 2010 |
| Last Modified: | 05 Dec 2017 17:11 |
| URI: | http://srodev.sussex.ac.uk/id/eprint/2466 |
| Google Scholar: | 12 Citations |