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Effects of tumor treating fields (TTFields) on gastric cancer cells and their potential concomitant application with FOLFOX
Background
Gastric cancer is one of the most common types of cancers worldwide, with the intestinal pathological variant common among elderly men, and the diffuse type common in woman and individuals under the age of 50. FOLFOX (oxaliplatin, fluorouracil [5-FU], and leucovorin) is an approved chemotherapy regimen for the treatment of gastric cancer. Despite advances in systemic therapies, long-term survival in gastric cancer remains poor. TTFields are alternating electrical fields that display an antimitotic effect on cancer cells. Recently, TTFields have also been shown to induce DNA damage in cancerous cells. The current study aimed to examine in vitro the efficacy and mechanism of action of TTFields for treating gastric cancer, and the potential of application of TTFields concomitant with FOLFOX.
Methods
Human gastric cell lines AGS (intestinal type) and KATO III (diffuse type) were treated with Tumor Treating Fields (TTFields) (1.1 and 1.7 V/cm, respectively) for 72 h at frequencies of 100–400 kHz using the inovitro system. The effectiveness of optimal frequency TTFields was evaluated by cell count, colony forming assay and apoptosis detection kit. Fluorescent staining for α-tubulin and phospho-histone 3 (PH3) was performed to detect defects in the mitotic spindle and chromosomes miss-localization, respectively; and phospho-histone H2AX (γH2AX) was stained to examine formation of DNA double strand breaks. Effectiveness of TTFields co-application with FOLFOX and its individual therapeutic components, oxaliplatin and 5-FU, was also tested.
Results
TTFields frequency leading to the largest cell count reduction in both cell lines was 150 kHz. TTFields at this frequency also resulted in decreased clonogenic potential and elevated apoptosis. The structural properties of the mitotic spindles of cells in mitosis, as seen from tubulin and DNA arrangement, revealed that under TTFields application most of the dividing cells displayed abnormal mitosis. Increased levels of γH2AX foci formation was also seen within cells that were exposed to TTFields, indicative of damage to the DNA. The efficacy of FOLFOX and its active components oxaliplatin and 5-FU was elevated by concomitant TTFields application.
Conclusions
TTFields at an optimal frequency of 150 kHz show potential as an effective gastric cancer treatment, impairing cellular mitosis and increasing DNA damage. Application of TTFields together with standard-of-care chemotherapy may further enhance efficacy.
Legal entity responsible for the study
The authors.
Funding
Novocure Ltd.
Disclosures
E. Zeevi: Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Ltd. E. Dor-On: Leadership role: Novocure Ltd; Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Ltd. R. Schneiderman: Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Ltd. M. Munster: Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Ltd. Y. Porat: Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Israel. T. Voloshin: Full / Part-time employment: Novocure Ltd. S. Davidi: Full / Part-time employment: Novocure Ltd. A. Haber: Shareholder / Stockholder / Stock options: Novocure LTD; Full / Part-time employment: Novocure LTD. M. Giladi: Leadership role: Novocure Ltd; Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Ltd. U. Weinberg: Leadership role: Novocure Ltd; Shareholder / Stockholder / Stock options: Novocure Ltd; Full / Part-time employment: Novocure Ltd. Y. Palti: Shareholder / Stockholder / Stock options: Novocure; Officer / Board of Directors: Novocure. All other authors have declared no conflicts of interest.
