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1.  Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells 
Scientific Reports  2015;5:18046.
Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields. TTFields are a unique anti-mitotic treatment modality delivered in a continuous, noninvasive manner to the region of a tumor. It was previously postulated that by exerting directional forces on highly polar intracellular elements during mitosis, TTFields could disrupt the normal assembly of spindle microtubules. However there is limited evidence directly linking TTFields to an effect on microtubules. Here we report that TTFields decrease the ratio between polymerized and total tubulin, and prevent proper mitotic spindle assembly. The aberrant mitotic events induced by TTFields lead to abnormal chromosome segregation, cellular multinucleation, and caspase dependent apoptosis of daughter cells. The effect of TTFields on cell viability and clonogenic survival substantially depends upon the cell division rate. We show that by extending the duration of exposure to TTFields, slowly dividing cells can be affected to a similar extent as rapidly dividing cells.
doi:10.1038/srep18046
PMCID: PMC4676010  PMID: 26658786
2.  NovoTTF™-100A System (Tumor Treating Fields) transducer array layout planning for glioblastoma: a NovoTAL™ system user study 
Background
Optune™, previously known as the NovoTTF-100A System™, generates Tumor Treating Fields (TTFields), an effective anti-mitotic therapy for glioblastoma. The system delivers intermediate frequency, alternating electric fields to the supratentorial brain. Patient therapy is personalized by configuring transducer array layout placement on the scalp to the tumor site using MRI measurements and the NovoTAL System. Transducer array layout mapping optimizes therapy by maximizing electric field intensity to the tumor site. This study evaluated physician performance in conducting transducer array layout mapping using the NovoTAL System compared with mapping performed by the Novocure in-house clinical team.
Methods
Fourteen physicians (7 neuro-oncologists, 4 medical oncologists, and 3 neurosurgeons) evaluated five blinded cases of recurrent glioblastoma and performed head size and tumor location measurements using a standard Digital Imaging and Communications in Medicine reader. Concordance with Novocure measurement and intra- and inter-rater reliability were assessed using relevant correlation coefficients. The study criterion for success was a concordance correlation coefficient (CCC) >0.80.
Results
CCC for each physician versus Novocure on 20 MRI measurements was 0.96 (standard deviation, SD ± 0.03, range 0.90–1.00), indicating very high agreement between the two groups. Intra- and inter-rater reliability correlation coefficients were similarly high: 0.83 (SD ±0.15, range 0.54–1.00) and 0.80 (SD ±0.18, range 0.48–1.00), respectively.
Conclusions
This user study demonstrated an excellent level of concordance between prescribing physicians and Novocure in-house clinical teams in performing transducer array layout planning. Intra-rater reliability was very high, indicating reproducible performance. Physicians prescribing TTFields, when trained on the NovoTAL System, can independently perform transducer array layout mapping required for the initiation and maintenance of patients on TTFields therapy.
doi:10.1186/s12957-015-0722-3
PMCID: PMC4642621  PMID: 26558989
Glioblastoma; Optune; NovoTAL System; NovoTTF-100A System; Tumor Treating Fields; TTFields
3.  ET-47TRIFLOUROPROMAZINE, AN APPROVED ANTIPSYCHOTIC DRUG, ENHANCES TUMOR TREATING FIELDS TREATMENT EFFICACY IN VITRO 
Neuro-Oncology  2014;16(Suppl 5):v89.
Tumor Treating Fields (TTFields) are low intensity, intermediate frequency alternating electric fields that disrupt proper spindle microtubules arrangement thus leading to mitotic arrest and subsequent cancer cell death. TTFields treated cells could escape cell death by exiting mitosis and entering interphase without chromosome segregation or cell division, a process also known as mitotic slippage. Triflouropromazine (TFP) is a clinically approved antipsychotic drug of the phenothiazine class that was recently reported to display anti slippage properties. The aim of this work is to determine whether TFP could increase TTFields efficacy based on its anti slippage properties. For this purpose, cell survival, volume and clonogenic potential of human glioblastoma (U87, U118) and breast adenocarcinoma (MCF-7, MDA-MB-231) cell lines were assessed following treatment with TTFields (3 V/cm) with cell line specific optimal frequency, with or without TFP. The percentage of cells that underwent mitotic slippage was determined using immunofluorescence imaging. TTFields as single application lead to a significant decrease in cell counts (26-44% reduction of control) and to cell volume increase (113-127% of control) in all cell lines. While TFP treatment as single agent had no effect on cell growth or cell volume, the combined treatment of TTFields and TFP resulted in an additional decrease in cell counts (31-58% reduction of control), further increase in cell volume (122-162% of control) and a reduced clonogenic potential. Immunofluorescence images of cells treated with TTFields demonstrated a significant increase in the number of cells that underwent slippage as compared to control cells or cells treated with TFP. Surprisingly, cells treated with TTFields and TFP demonstrated no decrease in the number of cells that underwent slippage. These results suggest that TFP enhances TTFields efficacy not by the inhibition of mitotic slippage. Further studies are underway in order to reveal the mechanism underlying the enhanced effect.
doi:10.1093/neuonc/nou255.45
PMCID: PMC4218143
4.  NT-37A PHASE II RANDOMIZED STUDY OF NovoTTF THERAPY VERSUS SUPPORTIVE CARE IN NON-SMALL CELL LUNG CANCER PATIENTS WITH 1-5 BRAIN METASTASES FOLLOWING OPTIMAL STANDARD LOCAL TREATMENT 
Neuro-Oncology  2014;16(Suppl 5):v166.
BACKGROUND: NovoTTF Therapy is a non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. During mitosis Tumor Treating Fields (TTFields) interfere with the formation of the mitotic spindle and physically translocate charged organelles. TTFields inhibit proliferation of non-small cell lung cancer (NSCLC) in vitro and in vivo. THE EF-21 CLINICAL TRIAL DESIGN: Patients with 1-5 NSCLC brain metastases (BM) who initially received optimal local treatment to all metastases are randomized in a ratio of 1:1 to either NovoTTF Therapy or supportive care alone arms. Patients are followed-up monthly (brain MRI every 3 months). Patient in the control arm may cross over at time of recurrence in the brain. OBJECTIVES: The current trial is designed to study the safety, tolerability and efficacy of NovoTTF therapy in this patient population. ENDPOINTS: Median time to local and distant progression in the brain (primary), neurocognitive function, quality of life, toxicity, overall survival and overall progression free survival (secondary). MAJOR ELIGIBILITY CRITERIA: Diagnosis of BM from NSCLC with stable systemic cancer, 1-5 BM following optimal local therapy, optimal systemic therapy for NSCLC. TREATMENT: Continuous NovoTTF Therapy at 150 kHz, applied to the brain using the NovoTTF-100A(M) System. The System is a portable medical device delivering alternating electric fields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. STATISTICAL CONSIDERATIONS: This is a prospective, randomized (1:1), multicenter study for 60 patients, comparing the hazard of progression in the brain over time between both arms using the Kaplan-Meier method. This trial has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.35 in time to progression in the brain. Randomization is stratified by number of BM (single vs. 2-5) and WHO performance score (0-1 vs. 2).
doi:10.1093/neuonc/nou265.35
PMCID: PMC4218446
5.  Microbial Growth Inhibition by Alternating Electric Fields in Mice with Pseudomonas aeruginosa Lung Infection▿ †  
High-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growth in vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused by Pseudomonas aeruginosa in mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growth in vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripheral (skin) heating of about 2°C can contribute to bacterial growth inhibition in the lungs of mice. We suggest that the combination of alternating electric fields, together with the heat produced during their application, may serve as a novel antibacterial treatment modality.
doi:10.1128/AAC.01841-09
PMCID: PMC2916302  PMID: 20547811
6.  TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters 
BMC Cancer  2010;10:229.
Background
Exposure of cancer cells to chemotherapeutic agents may result in reduced sensitivity to structurally unrelated agents, a phenomenon known as multidrug resistance, MDR. The purpose of this study is to investigate cell growth inhibition of wild type and the corresponding MDR cells by Tumor Treating Fields - TTFields, a new cancer treatment modality that is free of systemic toxicity. The TTFields were applied alone and in combination with paclitaxel and doxorubicin.
Methods
Three pairs of wild type/MDR cell lines, having resistivity resulting from over-expression of ABC transporters, were studied: a clonal derivative (C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant sub-line EmtR1; human breast cancer cells MCF-7 and their mitoxantrone-resistant sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours with and without the chemotherapeutic agents. The numbers of viable cells in the treated cultures and the untreated control groups were determined using the XTT assay. Student t-test was applied to asses the significance of the differences between results obtained for each of the three cell pairs.
Results
TTFields caused a similar reduction in the number of viable cells of wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a similar increased reduction in cell survival of wild type and MDR cells. TTFields had no effect on intracellular doxorubicin accumulation in both wild type and MDR cells.
Conclusions
The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors.
doi:10.1186/1471-2407-10-229
PMCID: PMC2893108  PMID: 20492723
7.  Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs 
Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100–200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.
doi:10.1007/s10585-009-9262-y
PMCID: PMC2776150  PMID: 19387848
Tumor treating fields; Metastases; Immune response
8.  Microbial Growth Inhibition by Alternating Electric Fields ▿  
Antimicrobial Agents and Chemotherapy  2008;52(10):3517-3522.
Weak electric currents generated using conductive electrodes have been shown to increase the efficacy of antibiotics against bacterial biofilms, a phenomenon termed “the bioelectric effect.” The purposes of the present study were (i) to find out whether insulated electrodes that generate electric fields without “ohmic” electric currents, and thus are not associated with the formation of metal ions and free radicals, can inhibit the growth of planktonic bacteria and (ii) to define the parameters that are most effective against bacterial growth. The results obtained indicate that electric fields generated using insulated electrodes can inhibit the growth of planktonic Staphylococcus aureus and Pseudomonas aeruginosa and that the effect is amplitude and frequency dependent, with a maximum at 10 MHz. The combined effect of the electric field and chloramphenicol was found to be additive. Several possible mechanisms underlying the observed effect, as well as its potential clinical uses, are discussed.
doi:10.1128/AAC.00673-08
PMCID: PMC2565914  PMID: 18663026
9.  Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) 
Background
The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial.
Methods
Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients.
Results
The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months.
Conclusion
These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity.
doi:10.1186/1756-6649-9-1
PMCID: PMC2647898  PMID: 19133110
10.  The Effects of External Potassium and Long Duration Voltage Conditioning on the Amplitude of Sodium Currents in the Giant Axon of the Squid, Loligo pealei 
The Journal of General Physiology  1969;54(5):589-606.
Giant axons were voltage-clamped in solutions of constant sodium concentration (230 mM) and variable potassium concentrations (from 0 to 210 mM). The values of the peak initial transient current, Ip, were measured as a function of conditioning prepulse duration over the range from less than 1 msec to over 3 min. Prepulse amplitudes were varied from Em = -20 mv to Em = -160 mv. The attenuation of the Ip values in high [Ko] was found to vary as a function of time when long duration conditioning potentials were applied. In both high and low [Ko], Ip values which had reached a quasi-steady—state level within a few milliseconds following a few milliseconds of hyperpolarization were found to increase following longer hyperpolarization. A second plateau was reached with a time constant of about 100–500 msec and a third with a time constant in the range of 30 to 200 sec. The intermediate quasi-steady—state level was absent in K-free ASW solutions. Sodium inactivation curves, normalized to Ipmax values obtained at either the first or second plateaus, were significantly different in different [Ko]. The inactivation curves, however, tended to superpose after about 1 min of hyperpolarizing conditioning. The time courses and magnitudes of the intermediate and very slow sodium conductance restorations induced by long hyperpolarizing pulses are in agreement with those predicted from the calculated rates and magnitudes of [K+] depletion in the space between the axolemma and the Schwann layer.
PMCID: PMC2225945  PMID: 5346530
11.  The Influence of External Potassium on the Inactivation of Sodium Currents in the Giant Axon of the Squid, Loligo pealei 
The Journal of General Physiology  1969;53(6):685-703.
Isolated giant axons were voltage-clamped in seawater solutions having constant sodium concentrations of 230 mM and variable potassium concentrations of from zero to 210 mM. The inactivation of the initial transient membrane current normally carried by Na+ was studied by measuring the Hodgkin-Huxley h parameter as a function of time. It was found that h reaches a steady-state value within 30 msec in all solutions. The values of h∞, τh, αh,and βh as functions of membrane potential were determined for various [Ko]. The steady-state values of the h parameter were found to be inversely related, while the time constant, τh, was directly related to external K+ concentration. While the absolute magnitude as well as the slopes of the h∞ vs. membrane potential curves were altered by varying external K+, only the magnitude and not the shape of the corresponding τh curves was altered. Values of the two rate constants, αh and βh, were calculated from h∞ and τh values. αh is inversely related to [Ko] while βh is directly related to [Ko] for hyperpolarizing membrane potentials and is independent of [Ko] for depolarizing membrane potentials. Hodgkin-Huxley equations relating αh and βh to Em were rewritten so as to account for the observed effects of [Ko]. It is concluded that external potassium ions have an inactivating effect on the initial transient membrane conductance which cannot be explained solely on the basis of potassium membrane depolarization.
PMCID: PMC2202877  PMID: 5783008

Results 1-11 (11)