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In vitro evaluation of combined temozolomide and radiotherapy using X-rays and high-linear energy transfer radiation for glioblastoma

Barazzuol, L, Jena, R, Burnet, NG, Jeynes, JC, Merchant, MJ, Kirkby, KJ and Kirkby, NF (2012) In vitro evaluation of combined temozolomide and radiotherapy using X-rays and high-linear energy transfer radiation for glioblastoma Radiation Research, 177 (5). pp. 651-662.

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High linear energy transfer (LET) radiation offers superior biophysical properties over conventional radiotherapy and may have a great potential for treating radioresistant tumours, such as glioblastoma (GBM). However, very little pre-clinical data exists on the effects of high LET radiation on GBM cell lines and moreover on the concomitant application of chemotherapy. This study investigates the in vitro effects of temozolomide (TMZ) in combination with low-energy protons and alpha particles. Cell survival, DNA damage and repair, and cell growth were examined in four human GBM cell lines (LN18, T98G, U87 and U373) after treatment with either X-rays, protons (LET 12.91 keV/µm), or alpha particles (LET 99.26 keV/µm) concurrently with TMZ at clinically relevant doses of 25 and 50 µM. The relative biological effectiveness at 10% survival (RBE10) increased as LET increased: 1.17 and 1.06 for protons, and 1.84 and 1.68 for alpha particles in the LN18 and U87 cell lines, respectively. TMZ administration increased cell killing in the O6-methylguanine DNA methyltransferase (MGMT)-methylated U87 and U373 cell lines. In contrast, TMZ provided no therapeutic enhancement in the MGMT-unmethylated LN18 and T98G cell lines. The residual number of γ-H2AX foci at 24 h after treatment with radiation and concomitant TMZ was found to be lower than or equal to that expected by DNA damage with either of the individual treatments. The kinetics of foci disappearance after X-ray and proton irradiation followed similar time courses; whereas, the loss of γ-H2AX foci following alpha particle irradiation occurred at a slower rate than that by low LET radiation (half-life 12.51-16.87 h). The combination of TMZ with different radiation types causes additive rather than synergistic cytotoxicity. Nevertheless, particle therapy combined with chemotherapy may offer a promising alternative with the additional benefit of superior biophysical properties. It is also possible that new fractionation schedules could be designed to exploit the change in the DNA repair kinetics when MGMT-methylated cells respond to high LET radiation.

Item Type: Article
Authors :
Barazzuol, L
Jena, R
Burnet, NG
Jeynes, JC
Merchant, MJ
Kirkby, KJ
Kirkby, NF
Date : 1 May 2012
DOI : 10.1667/RR2803.1
Depositing User : Symplectic Elements
Date Deposited : 28 Mar 2017 15:00
Last Modified : 31 Oct 2017 14:18

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