Tumor Treating Fields (150 kHz) combined with FOLFOX inhibits gastric cancer in vitro

Abstract

Introduction: Gastric cancer is the fourth most common cancer and the second most common cause of cancer death worldwide. Despite recent improvements in systemic therapies, long‐term survival rates for patients with advanced gastric cancer remains poor. Tumor Treating Fields (TTFields) therapy is an approved anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is a loco-regional treatment that targets rapidly dividing cells by disrupting microtubules leading to mitotic catastrophe, abnormal chromosome segregation and the induction of various forms of cancer cell death. FOLFOX (Oxaliplatin, 5-FU and Leucovorin) is an approved chemotherapy regimen for gastric cancer. We investigated the potential use of TTFields alone and in combination with FOLFOX for gastric carcinomas. Methods: AGS and KATO III gastric cells were treated for 72 hours with TTFields (1.1 and 1.7 V/cm, respectively) at various frequencies using the in-vitro system. Efficacy of the combined treatment of TTFields and FOLFOX and its individual components was tested by applying TTFields at the optimal frequency in combination with various drug concentrations. Cell counts, induction of apoptosis, clonogenic potential and overall effect were determined at the end of treatment. Results: The optimal TTFields frequency leading to the highest reduction in cell counts was 150 kHz for both cell lines: 55% and 52% reduction in cell counts for AGS and KATO III, respectively. The clonogenic potential of both cell lines was reduced by more than 70%. The combined treatment of TTFields with each FOLFOX component (Oxaliplatin, 5-FU or Leucovorin) led to a significant reduction in the survival of AGS and KATO III cells (2-way ANOVA, p < 0.001 for both cell lines) as compared to each treatment alone. The combined treatment of TTFields with FOLFOX led to further reduction in the overall effect (cytotoxic and clonogenic) of AGS (79%) compared to TTFields alone (65%) and FOLFOX alone (34%). Similar results were observed for the combined treatment of TTFields and FOLFOX in KATO III cells. Conclusion: These results presented demonstrate that TTFields can be an effective treatment against gastric cancer. The combination of TTFields with FOLFOX may further enhance treatment efficacy. There is a strong rationale to continue exploring the potential use of TTFields in combination with standard of care for the treatment of gastric cancer in the clinical settings.