The online version of this article (https://doi.org/10.1186/s13014-017-0941-6) contains supplementary material, which is available to authorized users.
Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.
The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).
TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the “skin sparing effect”. Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.
Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.
Additional file 1: Table S1. RT treatment schedule and transducer replacement schedule. Rats received RT on days 0-4 and 7-11 (indicated by V). Groups 4 and 5 had arrays placed on their dorsal surface (arrays where replaced days indicated by V). Rats where euthanized on day 12. (DOCX 96 kb)
Additional file 2: Figure S1. TTFields effect on LN-18 glioma cells. Surviving fractions of LN-18 cells treated with TTFields (200 kHz, 1.0 V/cm) for 72 h either alone or immediately after irradiation with 4 Gy (A). Surviving fraction of LN-18 cells treated with RT alone or with RT at various doses followed by 200 kHz TTFields (1.0 V/cm RMS) for 72 h. Results of the combined treatments were normalized to the effect of TTFields alone (B). (PPTX 2783 kb)
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- Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells
Rosa S. Schneiderman
Eilon D. Kirson
- BioMed Central
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