In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso

Blatt, Roni; Davidi, Shiri; Munster, Mijal; Shteingauz, Anna; Cahal, Shay; Zeidan, Adel; Marciano, Tal; Bomzon, Zéev; Haber, Adi; Giladi, Moshe; Weinberg, Uri; Kinzel, Adrian; Palti, Yoram

doi:10.3389/fonc.2021.670809

Cited by 19 publications

(18 citation statements)

References 39 publications

(55 reference statements)

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“…On the other hand, in the experiments by Li et al, who studied a range of TTFields frequencies from 100–1000 kHz, the inhibition ratio of HeLa cell growth decreased as the frequency was increased, with the maximal growth inhibition observed for 100 kHz TTFields [ 53 ]. Our results are consistent with their findings that, for the HeLa cell line, lower frequencies of TTFields are more effective at reducing cell counts and hindering cell division—a result that is likely, at least in part, due to cell morphology [ 54 ].…”

Section: Discussionsupporting

confidence: 92%

“…As far as we are aware, this is the only study to date that has investigated the effects of TTFields on MCF-10A cells. Although there have been many successful clinical trials with TTFields, and their in vivo safety has been established in several studies [ 21 , 54 ], there are limited data available on the effects of TTFields on normal cells. In the recent work of Ye et al, it was found that TTFields applied to normal brain organoids in vitro induced cell damage that could lead to apoptosis [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

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

Staelens

Lazzari

et al. 2022

Cells

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The effects of electric fields (EFs) on various cell types have been thoroughly studied, and exhibit a well-known regulatory effect on cell processes, implicating their usage in several medical applications. While the specific effect exerted on cells is highly parameter-dependent, the majority of past research has focused primarily on low-frequency alternating fields (<1 kHz) and high-frequency fields (in the order of MHz). However, in recent years, low-intensity (1–3 V/cm) alternating EFs with intermediate frequencies (100–500 kHz) have been of topical interest as clinical treatments for cancerous tumours through their disruption of cell division and the mitotic spindle, which can lead to cell death. These aptly named tumour-treating fields (TTFields) have been approved by the FDA as a treatment modality for several cancers, such as malignant pleural mesothelioma and glioblastoma multiforme, demonstrating remarkable efficacy and a high safety profile. In this work, we report the results of in vitro experiments with HeLa and MCF-10A cells exposed to TTFields for 18 h, imaged in real time using live-cell imaging. Both studied cell lines were exposed to 100 kHz TTFields with a 1-1 duty cycle, which resulted in significant mitotic and cytokinetic arrest. In the experiments with HeLa cells, the effects of the TTFields’ frequency (100 kHz vs. 200 kHz) and duty cycle (1-1 vs. 1-0) were also investigated. Notably, the anti-mitotic effect was stronger in the HeLa cells treated with 100 kHz TTFields. Additionally, it was found that single and two-directional TTFields (oriented orthogonally) exhibit a similar inhibitory effect on HeLa cell division. These results provide real-time evidence of the profound ability of TTFields to hinder the process of cell division by significantly delaying both the mitosis and cytokinesis phases of the cell cycle.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Staelens

Lazzari

et al. 2022

Cells

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“…Animal housing and anesthesia as well as array composition and placement procedure were previously described [ 24 ]. Male SD rats (age: 7–8 weeks; weight: 150–200 g; Envigo Ltd., Jerusalem, Israel) were inoculated with N1-S1 cells (50,000 suspension in 10 µL serum free DMEM medium, diluted 1:1 in Matrigel) into the left hepatic lobe.…”

Section: Methodsmentioning

confidence: 99%

“…Throughout the study the rats were housed in individual cages to prevent tangling of the wires connected to the device. TTFields (2.4 V/cm RMS; 150 kHz; Novo-TTF100L device) were applied continuously for 5 days through two pairs of perpendicular arrays placed around the tumor, each pair applying unidirectional TTFields for 1 s intermittently [ 21 , 24 ]. Device usage data were recorded to ensure animals successfully received therapy for ≥18 h/day, as per clinical recommendations for maximizing treatment benefits [ 25 , 26 ].…”

Section: Methodsmentioning

confidence: 99%

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Davidi¹,

Jacobovitch²,

Shteingauz³

et al. 2022

Cancers

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Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, is a leading cause of cancer-related death. Tumor Treating Fields (TTFields) are electric fields that exert antimitotic effects on cancerous cells. The aims of the current research were to test the efficacy of TTFields in HCC, explore the underlying mechanisms, and investigate the possible combination of TTFields with sorafenib, one of the few front-line treatments for patients with advanced HCC. HepG2 and Huh-7D12 human HCC cell lines were treated with TTFields at various frequencies to determine the optimal frequency eliciting maximal cell count reduction. Clonogenic, apoptotic effects, and autophagy induction were measured. The efficacy of TTFields alone and with concomitant sorafenib was tested in cell cultures and in an orthotopic N1S1 rat model. Tumor volume was examined at the beginning and following 5 days of treatment. At study cessation, tumors were weighed and examined by immunohistochemistry to assess autophagy and apoptosis. TTFields were found in vitro to exert maximal effect at 150 kHz, reducing cell count and colony formation, increasing apoptosis and autophagy, and augmenting the effects of sorafenib. In animals, TTFields concomitant with sorafenib reduced tumor weight and volume fold change, and increased cases of stable disease following treatment versus TTFields or sorafenib alone. While each treatment alone elevated levels of autophagy relative to control, TTFields concomitant with sorafenib induced a significant increase versus control in tumor ER stress and apoptosis levels, demonstrating increased stress under the multimodal treatment. Overall, TTFields treatment demonstrated efficacy and enhanced the effects of sorafenib for the treatment of HCC in vitro and in vivo, via a mechanism involving induction of autophagy.

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“…Even cells that exhibit rapid cell division such as those found in bone marrow or intestine are not affected as they are protected by high impedance of the bone, and slower replication times compared to cancerous cells respectively. 6 Tight junctions between epithelial cells at the blood-brain barrier (BBB) are known to inhibit the influx and efflux of many molecules to the brain. 7,8 This barrier can be overcome by taking advantage of the leaky vasculature surrounding brain tumours which leads to the accumulation of NPs in the tumour, via the Enhanced Permeation and Retention (EPR) effect.…”

Section: Introductionmentioning

confidence: 99%

Electric Field Responsive Nanotransducers for Glioblastoma

Jain

Jobson

Griffin

et al. 2022

Preprint

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Electric field therapies such as Tumor Treating Fields (TTFields) have emerged as a bioelectronic treatment for isocitrate dehydrogenase wild-type and IDH mutant grade 4 astrocytoma Glioblastoma (GBM). TTFields rely on alternating current (AC) electric fields (EF) leading to the disruption of dipole alignment and induced dielectrophoresis during cytokinesis. Although TTFields have a favourable side effect profile, particularly compared to cytotoxic chemotherapy, survival benefits remain limited (~ 4.9 months) after an extensive treatment regime (20 hours/day for 18 months). The cost of the technology also limits its clinical adoption worldwide. Therefore, the discovery of new technology that can enhance survival benefit and improve the cost per added quality of life year per patient, of these TTFields will be of great benefit to cancer treatment and decrease healthcare costs worldwide. In this work, we report the role of electrically conductive gold (GNPs), dielectric silica oxide (SiO2), and semiconductor zinc oxide (ZnO) nanoparticles (NPs) as transducers for enhancing EF mediated anticancer effects on patient derived GBM cells. Physicochemical properties of these NPs were analyzed using spectroscopic, electron microscopy, and light-scattering techniques. In vitro TTFields studies indicated an enhanced reduction in the metabolic activity of patient-derived Glioma INvasive marginal (GIN 28) and Glioma contrast enhanced core (GCE 28) GBM cells in groups treated with NPs vs. control groups, irrespective of NPs dielectric properties. Our results indicate the inorganic NPs used in this work enhance the intracellular EF effects by virtue of bipolar dielectrophoretic and electrophoretic effects. This work presents preliminary evidence which could help to improve future EF applications for bioelectronic medicine. Furthermore, the merits of spherical morphology, excellent colloidal stability, and low toxicity, make these NPs ideal for future studies for elucidating the detailed mechanism and efficacy upon their delivery in GBM preclinical models.

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In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso

Cited by 19 publications

References 39 publications

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

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

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Electric Field Responsive Nanotransducers for Glioblastoma

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