Cytotoxic effects of temozolomide and radiation are additive- and schedule-dependent

Chalmers, A.J. , Ruff, E.M., Martindale, C., Lovegrove, N. and Short, S.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. (doi: 10.1016/j.ijrobp.2009.07.1703)

Abstract

<b>Purpose:</b> 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. <b>Methods and Materials:</b> 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). <b>Results:</b> 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. <b>Conclusions:</b> 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: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chalmers, Professor Anthony
• Authors: Chalmers, A.J., Ruff, E.M., Martindale, C., Lovegrove, N., and Short, S.C.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: International Journal of Radiation Oncology, Biology, Physics
• ISSN: 0360-3016