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

Journal Article · Tue Dec 01 00:00:00 EST 2009 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2009.07.1703· OSTI ID:21367564

Ruff, Elliot M ^[1]; Martindale, Christine ^[2]; Lovegrove, Nadia ^[3]; Short, Susan C ^[2]

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1. Royal Sussex County Hospital, Eastern Road, Brighton (United Kingdom)
2. UCL Cancer Institute, Paul O'Gorman Building, University College London, London (United Kingdom)
3. Genome Damage and Stability Centre, University of Sussex, Falmer (United Kingdom)

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 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.

• OSTI ID: 21367564
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 75, Issue 5; Other Information: DOI: 10.1016/j.ijrobp.2009.07.1703; PII: S0360-3016(09)02799-0; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
CAFFEINE
CELL CYCLE
CHEMOTHERAPY
DNA REPAIR
GLIOMAS
RADIOTHERAPY
TOXICITY
ANALEPTICS
AROMATICS
AZAARENES
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
CENTRAL NERVOUS SYSTEM AGENTS
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NEOPLASMS
NERVOUS SYSTEM DISEASES
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
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RADIOLOGY
REPAIR
THERAPY
XANTHINES