Effectiveness of a Fractionated Therapy Scheme in Tumor Treating Fields Therapy

Abstract

This study aimed to evaluate the biological effectiveness of cancer therapy with tumor treating fields using a fractionated treatment scheme that was originally designed for radiotherapy. Discontinuous fractional tumor treating fields of an intensity of 0.9 to 1.2 V/cm and a frequency of 150 KHz were applied to U373 cancer cells and IEC6 normal cells for 3 days, with durations of 3, 6, 12, or 24 h/d. As the treatment duration of the tumor treating fields increased from 3 to 24 h/d, the relative tumor cell (U373) number (% of control) reduced in proportion to the treatment duration. Compared to a 25% cell number reduction (75% of control) for the group of 6 h/d treatment at 1.2 V/cm, only 5% (70% of control) and 8% (67% of control) of additional reductions were observed for the group of 12 and 24 h/d treatment, respectively. This experimental result indicates that the dependence on treatment duration in tumor cell inhibition was weakened distinctly at treatment duration over 6 h/d. For normal cells (IEC6), the relative cell number corresponding to the treatment time of the tumor treating fields at 1.2 V/cm of electric field strength was not decreased much for the treatment times of 3, 6, and 12 h/d, revealing 93.3%, 90.0%, and 89.3% relative cell numbers, respectively, but it suddenly decreased to ∼73% for the 24 h/d treatment. Our results showed that the effects of tumor treating fields on tumor cells were higher than on normal cells for treatment duration of 3 to 12 h/d, but the difference became minimal for treatment duration of 24 h/d. The fractionated scheme, using tumor treating fields, reduced the treatment time while maintaining efficacy, suggesting that this method may be clinically applicable for cancer treatment.

Real-Time Monitoring of the Effect of Tumour-Treating Fields on Cell Division Using Live-Cell Imaging

“…Hence, our results on HeLa cells appear consistent with the claim that the optimal TTFields frequency is lower for larger cells. Additionally, findings indicate that cells with shorter doubling times are significantly more affected by TTFields [ 63 ]. This suggests that HeLa cells, which have a doubling time of ~33–35 h [ 64 ]—relatively similar to that of glioma (~23 h to a few days [ 65 , 66 , 67 ]) and mesothelioma (~30–72 h [ 68 ]) cells—should also be seriously affected by TTFields.…”

The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy

“…The dependence of duration on tumor cell suppression is significantly reduced when the duration exceeds 6 hours/day. Cytostatic effect appears indistinguishable for the same duration, no matter TTFields administered continuously or dividedly [ 57 ].…”

“…DNA damage repair and cell cycle arrest. TTFields inhibits tumor cells and causes DNA damage [ 62 ] but does not cause DNA double-strand breaks and cell cycle arrest in normal cells [ 57 , 61 ]. However, studies show that TTFields leads to G2/M arrest in IEC6 normal cells and tumor cells, but the increased degree varies with the duration of TTFields (0–24 hours/day) [ 57 ].…”

“…Within 12 hours treatment of TTFields, there is no significant change in IEC6 normal cells. Apoptosis cells slightly rise at 24 hours, but are far less than that of tumor cells [ 57 ]. When TTFields treats for 3–12 hours/day, the inhibition on normal cells and tumor cells is quite different.…”

“…TTFields alone or combined with hyperthermia or drugs such as Paclitaxel, Sorafenib, and MPS1-IN-3 (spindle assembly checkpoint inhibitor) increase apoptosis in glioma or GBM [ 26 , 32 , 45 , 49 , 55 , 57 , 64 , 65 ]. In general, the portion of apoptosis cells varies among cell lines, is positively related to the intensity [ 20 ].…”