Clinical Review Abstract
Trials in Progress Abstract
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Effect of tumor-treating fields on DNA repair in cancer cell lines.
2013 ASCO Annual Meeting
J Clin Oncol 31, 2013 (suppl; abstr e22138)
Author(s): Eilon David Kirson, Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Mijal Munster, Uri Weinberg, Yoram Palti; NovoCure, Haifa, Israel; NovoCure, Lausanne, Switzerland
Background: TTFields Therapy is an antimitotic treatment modality approved by FDA for the treatment of patients with recurrent glioblastoma (GBM). TTFields act by disruption of spindle microtubule arrangement during metaphase and interference with cytokinesis during anaphase and telophase. These effects are the result of rotation of charged and/or polar macromolecules in the direction of the applied antimitotic fields. We hypothesized that the negatively charged, double stranded DNA fragments induced by ionizing radiation (RT) or ultraviolet light (UV) undergo similar rotation. Double strand break repair relies on proper alignment of the strands during the process of homologous recombination. Thus application of TTFields during the DNA repair process holds the potential of interfering with normal DNA repair. Methods: Cancer cells (786-O renal cell carcinoma) were exposed to TTFields for various durations up to 4 hours after UV or RT treatment. The extent of DNA repair over time was evaluated using the alkaline comet assay (Trevigen, USA). This assay allows the computation of the relative proportion of intact DNA strands and DNA fragments in individual cells after inducing DNA breaks. Results: Exposure of UV treated cells to TTFields for 4 hours led to a significant increase in the content of DNA fragments per cell compared to the content without TTFields exposure (45 + 14%; p=0.012). This increase was accompanied by a significant decrease in the intact DNA content per cell compared to the content of cells not exposed to TTFields (47 + 14%; p=0.005). Inhibition of DNA repair was apparent 1-4 hours after irradiation depending on the extent of DNA damage. Similar results were seen after exposure of the cultures to 2Gy RT (17% increase in DNA fragment content and 14% decrease in intact DNA content at 4 hours). Interestingly, while TTFields did not lead to any DNA damage when applied alone, the application of TTFields for one hour after UV exposure led to a 27 + 29% (p=0.02) increase in the extent of the DNA damage (fragment content). Conclusions: This is the first demonstration that, in addition to its known anti-mitotic effect, TTFields Therapy also inhibits DNA repair and may thus lead to an increase in the cytotoxic effects of therapeutic irradiation.
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