Cytotoxic Effects of Temozolomide and Radiation are Additive- and Schedule-Dependent

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

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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: 30 Nov 2012 16:54
URI: http://sro.sussex.ac.uk/id/eprint/2466
Google Scholar:12 Citations
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