Disruption of cancer cell replication by alternating electric fields
Open accessAbstract
Low-intensity, intermediate-frequency (100-300 kHz), alternating electric fields, delivered by means of insulated electrodes, were found to have a profound inhibitory effect on the growth rate of a variety of human and rodent tumor cell lines (Patricia C, U-118, U-87, H-1299, MDA231, PC3, B16F1, F-98, C-6, RG2, and CT-26) and malignant tumors in animals. This effect, shown to be nonthermal, selectively affects dividing cells while quiescent cells are left intact. These fields act in two modes: arrest of cell proliferation and destruction of cells while undergoing division. Both effects are demonstrated when such fields are applied for 24 h to cells undergoing mitosis that is oriented roughly along the field direction. The first mode of action is manifested by interference with the proper formation of the mitotic spindle, whereas the second results in rapid disintegration of the dividing cells. Both effects, which are frequency dependent, are consistent with the computed directional forces exerted by these specific fields on charges and dipoles within the dividing cells. In vivo treatment of tumors in C57BL/6 and BALB/c mice (B16F1 and CT-26 syngeneic tumor models, respectively), resulted in significant slowing of tumor growth and extensive destruction of tumor cells within 3-6 days. These findings demonstrate the potential applicability of the described electric fields as a novel therapeutic modality for malignant tumors.
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Claims the paper makes
5 of 18 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
The nuclear rotation effect resembles the whole-cell rotation previously described during exposure to intermediate-frequency alternating electric fields.
“This effect resembles the whole-cell rotation previously described during exposure to intermediate-frequency alternating electric fields (7,8).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [7] Zimmermann U, Vienken J, Pilwat G Rotation of cells in an alternating electric field: the occurrence of a resonance frequency. Z Naturforsch C, 36: 173-7, 1981. source
- cites [8] Holzapfel C, Vienken J, Zimmermann U Rotation of cells in an alternating electric field: theory and experimental proof. J Membr Biol, 67: 13-26, 1982. source
- Findingcitation
TTFields caused dividing cells to orient in the direction of the applied field.
“Also, TTFields caused the dividing cells to orient in the direction of the applied field in a manner similar to that described in cultured human corneal epithelial cells exposed to constant electric fields (17).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [17] Zhao M, Forrester JV, McCaig CD A small, physiological electric field orients cell division. Proc Natl Acad Sci USA, 96: 4942-6, 1999. source
- Interpretationcitation
The abnormal mitotic configurations seen after TTFields exposure are similar to morphological abnormalities seen in cells treated with agents that interfere directly or indirectly with microtubule polymerization (e.g., Taxol).
“TTFields are similar to the morphological abnormalities seen in cells treated with agents that interfere directly (18,19) or indirectly (20 -22) with microtubule polymerization (e.g., Taxol).”
Quote in the paperNot a substantial claim2 of 5 sources checked- cites [18] Jordan MA, Thrower D, Wilson L Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles: implications for the role of microtubule dynamics in mitosis. J Cell Sci, 102: 401-16, 1992. source
- cites [19] Rowinsky EK, Donehower RC Paclitaxel (Taxol). N Engl J Med, 332: 1004-14, 1995. source
- cites [20] Kline-Smith SL, Walczak CE The microtubule-destabilizing kinesin XKCM1 regulates microtubule dynamic instability in cells. Mol Biol Cell, 13: 2718-31, 2002. source
- cites [21] Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol, 150: 975-88, 2000. source
The Results section (‘Monastrol Inhibits Centrosome Separation Not Duplication’; page unavailable) reports that monastrol produces abnormal monoastral spindles by inhibiting centrosome separation. The Discussion (‘Monastrol Is a Reversible and Specific Probe for Eg5-dependent Mitotic Processes’; page unavailable) says monastrol does not affect tubulin polymerization in vitro, so the paper supports the morphological example but not the characterization of monastrol as interfering with microtubule polymerization. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [22] Maiato H, Sampaio P, Lemos CL, et al MAST/Orbit has a role in microtubule-kinetochore attachment and is essential for chromosome alignment and maintenance of spindle bipolarity. J Cell Biol, 157: 749-60, 2002. source
The Results sections on MAST RNAi report abnormal mitotic configurations, including monopolar spindles and misaligned chromosomes. The Discussion proposes that MAST/Orbit may affect microtubule plus-end stabilization, but treats that mechanism as uncertain. The paper does not compare these abnormalities with TTFields exposure; it supports the cited example of abnormal spindle morphology, not the comparison or a definite effect on polymerization. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Findingreasoning
Both effects of TTFields are frequency dependent.
“Both effects, which are frequency dependent, are consistent with the computed directional forces exerted by these specific fields on charges and dipoles within the dividing cells.”
Quote in the paperSubstantial claim - Findingreasoning
The first mode of TTField action is manifested by interference with the proper formation of the mitotic spindle.
“The first mode of action is manifested by interference with the proper formation of the mitotic spindle, whereas the second results in rapid disintegration of the dividing cells.”
Quote in the paperSubstantial claim- Rests on an assumption: Dividing cells contain highly polar, spatially oriented microtubules and develop a directional, hourglass-shaped morphology during cytokinesis.
- Findingown data
TTFields act by arresting cell proliferation.
“These fields act in two modes: arrest of cell proliferation and destruction of cells while undergoing division.”
- Also stated in: § INTRODUCTION · boosted
“We demonstrate that applying these fields to cancerous cells leads to proliferation arrest and cell destruction.”
Quote in the paperSubstantial claim - Also stated in: § INTRODUCTION · boosted
- Findingown data
TTFields inhibit malignant tumors in animals.
“Low-intensity, intermediate-frequency (100 -300 kHz), alternating electric fields, delivered by means of insulated electrodes, were found to have a profound inhibitory effect on the growth rate of a variety of human and rodent tumor cell lines (Patricia C, U-118, U-87, H-1299, MDA231, PC3, B16F1, F-98, C-6, RG2, and CT-26) and malignant tumors in animals.”
Quote in the paperSubstantial claim - Findingown data
TTFields act by destroying cells while they are undergoing division.
“These fields act in two modes: arrest of cell proliferation and destruction of cells while undergoing division.”
- Also stated in: § INTRODUCTION · boosted
“We demonstrate that applying these fields to cancerous cells leads to proliferation arrest and cell destruction.”
Quote in the paperSubstantial claim - Also stated in: § INTRODUCTION · boosted
- Findingown data
TTFields cause no significant side effects in syngeneic mice tumor models.
“When applied to syngeneic mice tumor models, these tumor treating fields (TTFields) cause a significant reduction in tumor growth rate without any significant side effects.”
Quote in the paperSubstantial claim - Findingown data
In all cell lines tested, 24-h exposure to TTFields at 100 kHz (1.0-1.4 V/cm) caused significant inhibition of cell proliferation (TER range 0.14-0.96; P<0.05).
“In all cell lines tested, 24-h exposure to TTFields at 100 kHz (at an intensity of 1.0 -1.4 V/cm) caused significant inhibition of cell proliferation (TER range, 0.14 -0.96; P Ͻ 0.05; Fig. 1C).”
Quote in the paperSubstantial claim - Findingnone given
The inhibitory effect of TTFields is nonthermal.
“This effect, shown to be nonthermal, selectively affects dividing cells while quiescent cells are left intact.”
Quote in the paperSubstantial claim - Findingown data
In vivo treatment of B16F1 and CT-26 syngeneic tumors in C57BL/6 and BALB/c mice significantly slows tumor growth.
“In vivo treatment of tumors in C57BL/6 and BALB/c mice (B16F1 and CT-26 syngeneic tumor models, respectively), resulted in significant slowing of tumor growth and extensive destruction of tumor cells within 3-6 days.”
- Also stated in: § INTRODUCTION · plain
“When applied to syngeneic mice tumor models, these tumor treating fields (TTFields) cause a significant reduction in tumor growth rate without any significant side effects.”
Quote in the paperSubstantial claim - Also stated in: § INTRODUCTION · plain
- Findingown data
In vivo TTField treatment extensively destroys tumor cells within 3-6 days.
“In vivo treatment of tumors in C57BL/6 and BALB/c mice (B16F1 and CT-26 syngeneic tumor models, respectively), resulted in significant slowing of tumor growth and extensive destruction of tumor cells within 3-6 days.”
Quote in the paperSubstantial claim - Findingreasoning
The second mode of TTField action results in rapid disintegration of dividing cells.
“The first mode of action is manifested by interference with the proper formation of the mitotic spindle, whereas the second results in rapid disintegration of the dividing cells.”
Quote in the paperSubstantial claim - Findingown data
Very low-intensity (<2 V/cm), intermediate-frequency (100-300 kHz), alternating electric fields induced by insulated electrodes have specific inhibitory effects on dividing cells in culture.
“In the present study we show for the first time, to our knowledge, that very low-intensity (Ͻ2 V/cm), intermediate-frequency (100 -300 kHz), alternating electric fields induced by insulated electrodes have specific inhibitory effects on dividing cells in culture.”
Quote in the paperSubstantial claim - Findingown data
Low-intensity, intermediate-frequency (100-300 kHz) alternating electric fields delivered by insulated electrodes inhibit the growth rate of a variety of human and rodent tumor cell lines.
“Low-intensity, intermediate-frequency (100 -300 kHz), alternating electric fields, delivered by means of insulated electrodes, were found to have a profound inhibitory effect on the growth rate of a variety of human and rodent tumor cell lines (Patricia C, U-118, U-87, H-1299, MDA231, PC3, B16F1, F-98, C-6, RG2, and CT-26) and malignant tumors in animals.”
Quote in the paperSubstantial claim - Findingown data
In BHK cultures maintained in low-serum (0.1% FCS) conditions to slow replication, 24-h exposure to 100 kHz TTFields at 1.2 V/cm produced no significant difference in cell number between control and treated cultures (P=0.97).
“No significant difference in cell number between control and TTField-treated cultures was observed under these con-ditions (P ϭ 0.97).”
Quote in the paperSubstantial claim - Findingown data
After returning BHK cultures to normal media (10% FCS), normal replication resumed both in cultures exposed to TTFields and in control cultures.
“After returning these cultures to normal media (10% FCS), normal replication resumed both in cultures exposed to TTFields and in control cultures.”
Quote in the paperSubstantial claim - Findingreasoning
For a cleavage furrow that reached a diameter of 1 m in an external field of only 1 V/cm, the force exerted on the microtubules is in the order of 5 pN.
“For example, for a cleavage furrow that reached a diameter of 1 m in an external field of only 1 V/cm, the force exerted on the microtubules is in the order of 5 pN.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Findingown data
In TTField-treated melanoma cultures, one-fourth of cells undergoing mitosis were destroyed as the formation of the cleavage furrow approached complete cell separation.
“The second major phenomenon, seen in the TTField-treated melanoma cultures, was that one-fourth of cells undergoing mitosis were destroyed as the formation of the cleavage furrow approached complete cell separation.”
Quote in the paperSubstantial claim - Findingown data
In TTField-treated mouse melanoma cultures, the most pronounced phenomenon was prolongation of mitosis.
“The most pronounced phenomenon was prolongation of mitosis.”
Quote in the paperSubstantial claim - Findingown data
Histopathological analysis of treated melanoma tumors showed extensive necrosis with aggregations of kariorrhectic and kariolytic debris.
“Histopathological analysis of treated tumors showed extensive necrosis with aggregations of kariorrhectic and kariolytic debris (Fig. 6F).”
Quote in the paperSubstantial claim - Findingown data
74% of the parallel oriented cells were damaged while being in metaphase.
“Moreover, 74% of the parallel oriented cells were damaged while being in metaphase (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
In TTField-treated melanoma cultures, more than one-half of the mitoses were abnormal.
“However, in TTFieldtreated cultures, more than one-half of the mitoses were abnormal.”
Quote in the paperSubstantial claim - Findingown data
No damage to the surrounding tissues was detected after TTField treatment in mice.
“No damage to the surrounding tissues was detected.”
Quote in the paperSubstantial claim - Findingown data
The inhibitory effect of TTFields on growth rate of cultured melanoma (B16F1) and glioma (F-98) cells was frequency dependent.
“As seen in Fig. 2C, the inhibitory effect of TTFields was frequency dependent.”
Quote in the paperSubstantial claim - Findingown data
Live mitotic cells in fixed melanoma cultures after 24 h TTField treatment were randomly distributed in all sectors relative to the electric field direction.
“As seen in Fig. 4A, the live cells were randomly distributed in all sectors.”
Quote in the paperSubstantial claim - Findingown data
A much higher proportion of damaged mitotic cells had their axis of division oriented along the field: 56% at 0° versus an average of 15% in each of the other orientations.
“In contrast, a much higher proportion of the damaged cells had their axis of division oriented along the field: 56% at 0° versus an average of 15% in each of the other orientations.”
Quote in the paperSubstantial claim - Findingown data
The inhibitory effect of TTFields on proliferation increases with intensity in both melanoma and glioma cell types.
“The inhibitory effect of the TTFields on proliferation increases with intensity in both cell types.”
Quote in the paperSubstantial claim - Findingown data
In control melanoma cultures, 95% of cells undergoing mitosis exhibited the normal stages of mitosis with intact mitotic spindles.
“In control cultures, 95% of cells undergoing mitosis exhibited the normal stages of mitosis with intact mitotic spindles.”
Quote in the paperSubstantial claim - Findingown data
Staining for actin filaments showed no difference between TTField-treated and control cultures.
“In contrast, staining for actin filaments showed no difference between TTField-treated and control cultures.”
Quote in the paperNot a substantial claim - Findingown data
Nonproliferating cells and tissues were unaffected by TTFields.
“We have demonstrated this inhibitory effect in all proliferating cell types tested, whereas, nonproliferating cells and tissues were unaffected.”
Quote in the paperSubstantial claim - Findingcitation
During destruction of mitotic cells, the cell membrane ruptured and many small membrane blebs formed, resembling post-mitotic apoptotic cell death.
“During this process, the cell membrane ruptured, and many small membrane blebs formed, resembling post-mitotic apoptotic cell death (13).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Endlich B, Radford IR, Forrester HB, Dewey WC Computerized video time-lapse microscopy studies of ionizing radiation-induced rapid-interphase and mitosis-related apoptosis in lymphoid cells. Radiat Res, 153: 36-48, 2000. source
- Findingown data
The frequency at which maximal inhibition was achieved differed between cell types: 120 kHz for melanoma and approximately 200 kHz for glioma.
“Interestingly, the frequency at which maximal inhibition was achieved differed between cell types (120 kHz versus ϳ200 kHz for melanoma and glioma, respectively).”
Quote in the paperSubstantial claim - Findingnone given
Different types of cancerous cells showed specific intensity and frequency dependences of TTField inhibition.
“Interestingly, different types of cancerous cells showed specific intensity and frequency dependences of TTField inhibition.”
Quote in the paperNot a substantial claim - Findingown data
There is increased field line concentration (increased field intensity) at the furrow during cytokinesis.
“We see an increased field line concentration (indicating increased field intensity) at the furrow, a phenomenon that highly resembles the focusing of a light beam by a lens.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Findingown data
Two examples of disintegration of TTFields-treated cells during cytokinesis were observed.
“B and C, two examples of disintegration of TTFields-treated cells during cytokinesis.”
Quote in the paperNot a substantial claim - Findingown data
At all stages of mitosis, a higher fraction of damaged cells had their axis of division oriented along the field.
“At all stages, a higher fraction of damaged cells had their axis of division oriented along the field.”
Quote in the paperSubstantial claim - Findingown data
The number of cells per unit area in the two 45° sectors was one-half that in the 0° sector.
“Surprisingly, the number of cells per unit area in the two 45° sectors was found to be one-half that in the 0° sector.”
Quote in the paperSubstantial claim - Findingown data
100-200 kHz TTFields at low intensities of <2 V/cm effectively inhibited malignant melanoma growth compared with nontreated control tumors in mice.
“We found that 100 -200 kHz of TTFields at low intensities of Ͻ2 V/cm effectively inhibited malignant melanoma growth compared with the growth of nontreated control tumors.”
Quote in the paperSubstantial claim - Findingown data
The prolongation of mitosis in TTField-treated cultures is statistically significant (P<0.01, Mann-Whitney U test).
“This prolongation is statistically significant (P Ͻ 0.01, Mann-Whitney U test).”
Quote in the paperSubstantial claim - Findingown data
The nontumor structures of the dermis were morphologically intact in treated mice.
“The nontumor structures of the dermis are morphologically intact.”
Quote in the paperSubstantial claim - Findingown data
Treated melanoma tumors were significantly smaller than control tumors at the end of treatment (average treated tumor size was 47% of control tumor size; n = 78 mice, P < 0.001; Student's t test).
“Treated tumors were significantly smaller than control tumors at the end of treatment (average treated tumor size was 47% of control tumor size; n ϭ 78 mice, P Ͻ 0.001; Student's t test).”
Quote in the paperSubstantial claim - Findingown data
TTFields inhibit all proliferating cell types tested.
“We have demonstrated this inhibitory effect in all proliferating cell types tested, whereas, nonproliferating cells and tissues were unaffected.”
Quote in the paperSubstantial claim - Findingown data
The average effect of TTFields on adenocarcinoma-carrying mice was less dramatic than that on malignant melanoma.
“The average effect of TTFields on adenocarcinoma carrying mice was less dramatic than that seen for malignant melanoma (average treated tumor size was 73% of control tumor size at the end of treatment; n ϭ 14 mice).”
Quote in the paperNot a substantial claim - Findingown data
Only necrotic tissue and cellular debris were seen in the treated tumor.
“F, only necrotic tissue and cellular debris are seen in the treated tumor.”
Quote in the paperSubstantial claim - Findingown data
Temperature measurements made within culture dishes during treatment and on the skin above treated tumors in vivo showed no significant elevation in temperature compared with control cultures/mice.
“Indeed, temperature measurements made within culture dishes during treatment and on the skin above treated tumors in vivo, showed no significant elevation in temperature compared with control cultures/mice.”
Quote in the paperSubstantial claim - Findingown data
The increase in the number of treated melanoma and glioma cells over time is significantly smaller than that of control cells (P < 0.001).
“The increase in the number of treated melanoma (left) and glioma (right) cells over time is significantly smaller than control cells (P Ͻ 0.001).”
Quote in the paperSubstantial claim - Findingown data
In four segments of rat mesentery and four segments of rat diaphragm exposed to 100 kHz TTFields at 1.2 V/cm for 24 h, no differences were observed between the number of viable cells in treated tissues compared with control tissues (mesentery P=0.3; diaphragm P=0.54).
“No differences were observed between the number of viable cells in both types of treated tissues compared with control tissues (mesentery, P ϭ 0.3; diaphragm, P ϭ 0.54).”
Quote in the paperSubstantial claim - Findingown data
The damage caused by TTFields to replicating cells is dependent on the orientation of the division process in relation to the field vectors.
“The damage caused by TTFields to these replicating cells was shown to be dependent on the orientation of the division process in relation to the field vectors, indicating that this effect is nonthermal.”
Quote in the paperSubstantial claim - Premisecitation
At very high frequencies (above many MHz), tissue heating becomes dominant due to dielectric losses.
“At very high frequencies (i.e., above many MHz), although the integration becomes even more effective, a completely different biological effect is observed.At these frequencies tissue heating becomes dominant due to dielectric losses.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Elson E Biologic effects of radiofrequency and microwave fields: in vivo and in vitro experimental results Bronzino JD eds. . The biomedical engineering handbook, p. 1417-23, CRC Press, Inc. Boca Raton, FL 1995.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
At the optic densities used (0.2-2), optic density was linearly related to the number of cells in the culture dishes (n=10; r2=0.99).
“At the optic densities used (0.2-2), optic density was linearly related to the number of cells in the culture dishes (n ϭ 10; r 2 ϭ 0.99).”
Quote in the paperSubstantial claim - Interpretationown data
The described electric fields have potential applicability as a novel therapeutic modality for malignant tumors.
“These findings demonstrate the potential applicability of the described electric fields as a novel therapeutic modality for malignant tumors.”
Quote in the paperSubstantial claim - Interpretationreasoning
The effects of TTFields are consistent with computed directional forces exerted by these fields on charges and dipoles within dividing cells.
“Both effects, which are frequency dependent, are consistent with the computed directional forces exerted by these specific fields on charges and dipoles within the dividing cells.”
Quote in the paperSubstantial claim- The authors state this as an assumption: At the relatively low frequencies used (100 kHz), the complex dielectric constant of the particle is greater than that of the cytoplasm, so the Clausius-Mossotti factor is always positive.
- Rests on an assumption: The force exerted by an electric field on a dipole is maximal when the dipole is oriented in the direction of the field.
- The authors state this as an assumption: The simplified description of cell morphology used in the finite element calculations adequately represents the cells.
- Interpretationown data
This finding may serve as an indication of an additional effect of TTFields: orientation of the cell division in the field direction.
“This finding may serve as an indication of an additional effect of TTFields: orientation of the cell division in the field direction.”
Quote in the paperNot a substantial claim- Rests on an assumption: The force exerted by an electric field on a dipole is maximal when the dipole is oriented in the direction of the field.
- Interpretationown data
The effect of TTFields on replicating cells is nonthermal.
“The damage caused by TTFields to these replicating cells was shown to be dependent on the orientation of the division process in relation to the field vectors, indicating that this effect is nonthermal.”
Quote in the paperSubstantial claim - Interpretationown data
When properly tuned, very low-intensity, intermediate-frequency electric fields (TTFields) stunt the growth of cancerous cells.
“In this study, we have shown that when properly tuned, very low-intensity, intermediate-frequency electric fields (TTFields) stunt the growth of cancerous cells.”
Quote in the paperSubstantial claim - Interpretationown data
The calculated maximal force when the division axis is aligned with the field is consistent with the dependence of the destructive effect of TTFields on the angle between division axis and the field.
“This is consistent with the dependence of the destructive effect of TTFields on the angle between division axis and the field (Fig. 4).”
Quote in the paperSubstantial claim - Interpretationcitation
This effect can explain the mitotic arrest of TTField-treated cells.
“This effect can explain the mitotic arrest of TTField-treated cells (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Fishkind DJ, Silverman JD, Wang YL Function of spindle microtubules in directing cortical movement and actin filament organization in dividing cultured cells. J Cell Sci, 109: 2041-51, 1996. source
- Interpretationown data
The calculated dependence of the magnitude of the electric force on frequency is consistent with the experimentally determined frequency dependence of the inhibitory effect of TTFields on melanoma and glioma cell proliferation.
“In addition, the calculated dependence of the magnitude of this force on frequency (data not shown) is consistent with the experimentally determined frequency dependence of the inhibitory effect of TTFields on melanoma and glioma cell proliferation (Fig. 2C).”
Quote in the paperSubstantial claim - Interpretationown data
The electric forces acting on intracellular particles are maximal when the axis of division is aligned with the external field.
“We also found that the electric forces acting on intracellular particles are maximal when the axis of division is aligned with the external field.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Interpretationcitation
The calculated force magnitude of 5 pN is compatible with the reported forces necessary to stall microtubule polymerization, which is 4.3 pN.
“This magnitude is compatible with the reported forces necessary to stall microtubule polymerization that is 4.3 pN (25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Dogterom M, Yurke B Measurement of the force-velocity relation for growing microtubules. Science, 278: 856-60, 1997. source
- Interpretationown data
During the early phases of mitosis (pre-telophase), the electric field forces tubulin dimers positioned further than 14 nm away from the growing end of a microtubule to orient in the direction of the field.
“Within this framework, during the early phases of mitosis, i.e., in pre-telophase, when tubulin polymerization-depolymerization drives the proliferation process, the electric field forces any tubulin dimers, positioned further than 14 nm away from the growing end of a microtubule, to orient in the direction of the field (Fig. 7A).”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Interpretationown data
Evidence indicates that TTFields disrupt the normal polymerization-depolymerization process of microtubules during mitosis.
“At the subcellular level, we have found evidence indicating that TTFields disrupt the normal polymerizationdepolymerization process of microtubules during mitosis.”
Quote in the paperSubstantial claim - Interpretationown data
The second mechanism, which interferes with cell division and is most likely to play an important role in cell destruction, becomes dominant during cleavage.
“The second mechanism, which interferes with cell division and is most likely to play an important role in cell destruction, becomes dominant during cleavage.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Interpretationreasoning
The inhomogeneity in field intensity exerts a unidirectional electric force on all intracellular charged and polar entities, pulling them toward the furrow regardless of field polarity.
“This inhomogeneity in field intensity exerts a unidirectional electric force on all intracellular charged and polar entities, pulling them toward the furrow (regardless of field polarity).”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Interpretationown data
Finite element simulations identified two main mechanisms by which electric fields may affect dividing cells.
“We identified two main mechanisms by means of which the electric fields may affect dividing cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Interpretationcitation
The force moment (10^-5 pN) acting on the dimers is sufficient to interfere with the proper process of assembly and disassembly of microtubules essential for chromosome alignment and separation.
“This force moment, (10 Ϫ5 pN) acting on the dimers, is sufficient to interfere with the proper process of assembly and disassembly of microtubules that is essential for chromosome alignment and separation (23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Gagliardi LJ Electrostatic force in prometaphase, metaphase, and anaphase-A chromosome motions. Phys Rev E Stat Nonlin Soft Matter Phys, 66: 011901 2002. source
- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
- Classified as probably not a substantial claim. 4
- May combine two claims. 23
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA number of nonthermal effects of minor biological consequence have been reported even at low field intensities, including microscopic particle alignment and cell rotation.
“However, a number of nonthermal effects of minor biological consequence have been reported even at low field intensities.These include microscopic particle alignment (i.e., the pearl chain effect; Ref. 6) and cell rotation (7,8).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] Takashima S, Schwan HP Alignment of microscopic particles in electric fields and its biological implications. Biophys J, 47: 513-8, 1985. source
- cites [7] Zimmermann U, Vienken J, Pilwat G Rotation of cells in an alternating electric field: the occurrence of a resonance frequency. Z Naturforsch C, 36: 173-7, 1981. source
The Results (page not provided) report cell rotation in an alternating electric field and conclude that thermal effects are not its primary cause. They specify a threshold of 300–500 V/cm, however, and do not characterize rotation as occurring at low field intensities or as having minor biological consequence. The pearl-chain effect is cited separately in the citing sentence, so it is not the basis of this verdict. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [8] Holzapfel C, Vienken J, Zimmermann U Rotation of cells in an alternating electric field: theory and experimental proof. J Membr Biol, 67: 13-26, 1982. source
May combine two claims.
Findingown dataTTFields selectively affect dividing cells while quiescent cells are left intact.
“This effect, shown to be nonthermal, selectively affects dividing cells while quiescent cells are left intact.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth the arrest and destruction effects are demonstrated when TTFields are applied for 24 h to cells undergoing mitosis oriented roughly along the field direction.
“Both effects are demonstrated when such fields are applied for 24 h to cells undergoing mitosis that is oriented roughly along the field direction.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUnder control conditions, most of the cell lines had doubling times of less than 24 h (range 17-24 h), except PC-3 for which the doubling time was 73 h.
“Because under control conditions, most of the cell lines had doubling times of less than 24 h (range, 17-24 h; except for PC-3 for which the doubling time was 73 h), treatment duration was at least 24 h.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTTField treatment produced abnormal mitotic forms including polypoid cells in prophase, ill-separated, multi-spindled and single-spindled cells in metaphase, asymmetric anaphases, and a large proportion of metaphase cells (>20%) with rosette-shaped chromosome assemblies.
“These included polypoid cells in prophase, ill-separated, multi-spindled and single-spindled cells in metaphase, asymmetric anaphases, and a large proportion of cells in metaphase (Ͼ20%) with rosette shaped chromosome assemblies.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn BALB/c mice with intradermal adenocarcinomas treated with the same field parameters, the average treated tumor size was 73% of control tumor size at the end of treatment (n = 14 mice).
“The average effect of TTFields on adenocarcinoma carrying mice was less dramatic than that seen for malignant melanoma (average treated tumor size was 73% of control tumor size at the end of treatment; n ϭ 14 mice).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe inhibitory effect of TTFields lasted beyond the exposure time; in some experiments (e.g., malignant melanoma), culture growth was stunted for as long as 72 h after TTField exposure was terminated.
“This effect lasted beyond the exposure time of the cells to TTFields.In fact in some experiments (e.g., malignant melanoma), culture growth was stunted for as long as 72 h after TTField exposure was terminated (Fig. 2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn simulations, the electric field within quiescent cells is homogenous, whereas the field inside mitotic cells during cytokinesis is not homogenous.
“As seen in the simulations depicted in Fig. 7B, the electric field within quiescent cells is homogenous, whereas the field inside mitotic cells, during cytokinesis, is not homogenous.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
May combine two claims.
Findingown dataIn all four animal cell lines and seven human cell lines tested, TTFields (100 kHz, 1-1.4 V/cm) inhibited growth rate compared with temperature-matched controls, and all effects were statistically significant (P < 0.05; Student's t test).
“In all four animal cell lines (Ⅺ) and seven human cell lines (f) tested, the ratio is greater than 0, indicating an inhibition in the growth rate of the treated cultures compared with temperature matched controls.All effects were statistically significant (P Ͻ 0.05; Student's t test).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn TTField-treated cultures, mitosis lasted on average 124 ± 91 min (mean ± SD, n=53; range 40-541 min), whereas under control conditions average mitosis duration was 62 ± 8 min (mean ± SD, n=12; range 47-78 min).
“Due to this proliferation arrest, in treated cultures, mitosis lasted on average 124 Ϯ 91 min (mean Ϯ SD, n ϭ 53; range, 40 -541 min), whereas under control conditions, average mitosis duration was 62 Ϯ 8 min from cell rounding to cytokinesis (mean Ϯ SD, n ϭ 12; range, 47-78 min).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn TTField-treated cultures, nuclear rotation occurred in early mitosis after cell rounding, with a full rotation lasting on average 15 min.
“The third phenomenon, seen only in TTField-treated cultures, was nuclear rotation.In early mitosis, after cell rounding, nuclei could be seen rotating within the cell.A full rotation lasted on average 15 min.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataA cell in mitosis was arrested by TTFields; contrary to normal mitosis, which lasts less than 1 h, the depicted cell was stationary at mid-cytokinesis for 3 h.
“A, an example of a cell in mitosis arrested by TTFields.Contrary to normal mitosis, the duration of which is less than 1 h, the depicted cell is seen to be stationary at mid-cytokinesis for 3 h.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataComplete proliferation arrest (TER = 1) is seen at 1.35 V/cm in melanoma cells and 2.25 V/cm in glioma cells.
“Complete proliferation arrest (TER ϭ 1) is seen at 1.35 and 2.25 V/cm in melanoma and glioma cells, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter 4 days of TTFields treatment at 100 kHz, no tumor could be discerned on the treated side, whereas on the untreated side a large tumor had grown.
“After 4 days of TTFields treatment (at 100 kHz), no tumor can be discerned on the treated side, whereas on the untreated side a large tumor has grown.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDestructive effects of TTFields were observed only in mitotic cells, whereas quiescent cells remained morphologically and functionally intact.
“Destructive effects were observed only in mitotic cells, whereas quiescent cells remained morphologically and functionally intact.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA window effect is seen with maximal inhibition by TTFields at 120 kHz in melanoma cells and at approximately 200 kHz in glioma cells.
“A window effect is seen with maximal inhibition by TTFields at 120 kHz in melanoma cells and at ϳ200 kHz in glioma cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn treated cells, mitosis seemed to begin normally but was prolonged for variable periods before completing cleavage into two daughter cells.
“In the treated cells, mitosis seemed to begin normally but was prolonged for variable periods of time before completing cleavage into two daughter cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe inhibitory effect of TTFields on proliferation of B16F1 melanoma and F-98 glioma cells increased as intensity was raised from 1 to 2.5 V/cm until complete proliferation arrest was achieved at 1.4 V/cm in melanoma and 2.25 V/cm in glioma cells.
“The inhibitory effect of TTFields on cell proliferation increased as intensity was raised (Fig. 2B) until complete proliferation arrest was achieved at intensities of 1.4 and 2.25 V/cm in melanoma and glioma cells, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTwo main processes occur at the cellular level during exposure to TTFields: arrest of proliferation and cell destruction.
“We have demonstrated that two main processes occur at the cellular level during exposure to TTFields: arrest of proliferation and cell destruction.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe voltage drop across a 100Ω resistor in series with a field-generating wire was linearly correlated to the field intensity (r2=0.96).
“The voltage drop on this resistor was linearly correlated to the field intensity (r 2 ϭ 0.96).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationIntermediate-frequency electric fields of low to moderate intensities are commonly considered to have no biological effect.
“Such fields of low to moderate intensities are commonly considered to have no biological effect (4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Elson E Biologic effects of radiofrequency and microwave fields: in vivo and in vitro experimental results Bronzino JD eds. . The biomedical engineering handbook, p. 1417-23, CRC Press, Inc. Boca Raton, FL 1995.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAt very low frequencies (under 1 kHz), alternating electric fields stimulate excitable tissues through membrane depolarization.
“At very low frequencies (under 1 kHz), alternating electric fields stimulate excitable tissues through membrane depolarization (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Polk C Therapeutic applications of low-frequency sinusoidal and pulsed electric and magnetic fields Bronzino JD eds. . The biomedical engineering handbook, p. 1404-16, CRC Press, Inc. Boca Raton, FL 1995.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisenone givenIntermediate-frequency electric fields (tens of kilohertz to megahertz) alternate too fast for causing nerve-muscle stimulation and involve only minute dielectric losses (heating).
“Intermediate-frequency electric fields (i.e., tens of kilohertz to megahertz) alternate too fast for causing nerve-muscle stimulation and involve only minute dielectric losses (heating).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataElectromagnetic radiation in the 100-300-kHz range within incubators containing treated culture dishes was 10^-12 Tesla and within animal cages containing TTField-treated mice was 10^-14 Tesla, i.e., negligible.
“The electromagnetic radiation in the 100 -300-kHz range within the incubators containing treated culture dishes was found to be 10 Ϫ12 Tesla and within animal cages containing TTField-treated mice, 10 Ϫ14 Tesla, i.e., negligible.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningCytoplasmic organelles are polarized by the field within dividing cells; once polarized, forces acting on such particles may reach values up to 60 pN, resulting in movement toward the furrow at velocities approaching 0.03 m/s.
“With regard to other particles such as cytoplasmatic organelles, they are polarized by the field within dividing cells.Once polarized, the forces acting on such particles may reach values up to an order of 60 pN resulting in their movement toward the furrow at velocities that may approach 0.03 m/s.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
May combine two claims.
Interpretationown dataTTFields inhibit both the proliferation of malignant cells in culture and the growth of tumors in mice while showing no general side effects or local histopathological damage.
“In conclusion, we have demonstrated that TTFields inhibit both the proliferation of malignant cells in culture and the growth of tumors in mice while showing no general side effects or local histopathological damage.”
Quote in the paperSubstantial claim- Rests on an assumption: The absence of local histopathological damage and observed acute effects in mice indicates no general side effects of TTFields.
May combine two claims.
Interpretationown dataThe mechanism of action of TTFields is, at least in part, dependent on disruption of the microtubules of the mitotic spindle and the electric forces resulting from focusing of the field in the dividing cells.
“The mechanism of action of the fields is, at least in part, dependent on disruption of the microtubules of the mitotic spindle and the electric forces resulting from focusing of the field in the dividing cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
May combine two claims.
InterpretationreasoningAt such velocity, cytoplasmic organelles would pile up at the cleavage furrow within a few minutes, interfering with cytokinesis and possibly leading to cell destruction.
“At such velocity, cytoplasmatic organelles would pile up at the cleavage furrow within a few minutes, interfering with cytokinesis and possibly leading to cell destruction.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
At the relatively low frequencies used (100 kHz), the complex dielectric constant of the particle is greater than that of the cytoplasm, so the Clausius-Mossotti factor is always positive.
“K() in this case is always positive at the relatively low frequencies used (i.e., 100 kHz), assuming that at these frequencies, ء⑀ p Ͼ ء⑀ m .”
The paper relies on this without support.
Dividing cells contain highly polar, spatially oriented microtubules and develop a directional, hourglass-shaped morphology during cytokinesis.
“One is that the latter contain highly polar, spatially oriented microtubules and that they develop a directional, hourglass-shaped cell morphology during the cytokinesis phase.”
The paper relies on this without support.
The force exerted by an electric field on a dipole is maximal when the dipole is oriented in the direction of the field.
“With regard to the latter, the force exerted by the field is maximal when the dipole is oriented in the direction of the field.”
The authors state this as an assumption.
The simplified description of cell morphology used in the finite element calculations adequately represents the cells.
“The calculations of the electric field within the cells are based on finite element mesh (11), using a simplified description of the cell morphology (see Fig. 7).”
The paper relies on this without support.
The absence of local histopathological damage and observed acute effects in mice indicates no general side effects of TTFields.
“In conclusion, we have demonstrated that TTFields inhibit both the proliferation of malignant cells in culture and the growth of tumors in mice while showing no general side effects or local histopathological damage.”
The paper relies on this without support.
The finite element simulations accurately represent the electric field distribution and forces inside real dividing cells.
“To explain how TTFields cause orientation-dependent damage to dividing cancerous cells and disrupt the proper formation of the mitotic spindle, we modeled the forces exerted by TTFields on intracellular charges and polar particles using finite element simulations (see”
The paper relies on this without support.
The effects of TTFields on cultured cancer cell lines and mouse tumor models are predictive of effects in human cancer patients.
“The highly specific effects of these fields on dividing cells, together with the relative ease of applying them, focusing them, and screening from them, make them an attractive candidate to serve as a novel treatment modality for cancer.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TTFields-induced mitotic spindle perturbations lead to abnormal chromosomal segregation, mitotic cell death, and perhaps apoptosis from cells that are able to exit mitosis.
“Such perturbations lead to abnormal chromosomal segregation, mitotic cell death, and perhaps apoptosis from cells that are able to exit mitosis [8,9,19].”
From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [9]
Induction of TTFields anti-mitotic effects requires electric field intensities above 1 V/cm RMS.
“Noteworthy, the duration of the invasion experiments and the applied electric fields intensities were shorter and lower than the duration and the intensities (above 1 V/cm RMS) required for induction of TTFields anti-mitotic effects [1,2].”
From Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics (2020) · cites this paper as [1]
Tumor Treating Fields (TTFields) are noninvasive alternating electric fields in the intermediate frequency range (100-300 kHz) used as an antimitotic cancer treatment.
“Tumor Treating Fields (TTFields) are noninvasive, alternating electric fields within the intermediate frequency range (100–300 kHz) that are utilized as an antimitotic cancer treatment.”
From Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics (2020) · cites this paper as [1]
In initial experiments, exposure of a variety of tumor cell lines to TTFields exerted a profound growth inhibitory effect by inducing cell cycle arrest and apoptosis, while no effect was induced on non-dividing cells.
“In initial experiments, exposure of a variety of tumor cell lines to TTFields was shown to exert a profound growth inhibitory effect by inducing cell cycle arrest and apoptosis, while no effect was induced on non-dividing cells.7”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [7]
Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200 kHz) that block cell division and interfere with organelle assembly.
“Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly.”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [7]
The optimal frequency to maximize the antitumor effect of TTFields is inversely correlated with cell size and when the incident angle of the electrical field is perpendicular to the mitotic plate.
“The optimal frequency to maximize the antitumor effect is inversely correlated with cell size and when the incident angle of the electrical field is perpendicular to the mitotic plate.7”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [7]
In telophase, the hourglass shape of daughter cells induces a nonuniform electric field enhanced at the furrow region, resulting in dielectrophoretic forces that may attract charged molecules from the cytosol and compromise normal cytokinesis.
“In telophase, during cytokinesis the hourglass shape taken by the daughter cells that are about to separate induces a nonuniform electric field that is strongly enhanced at the level of the furrow region (→ fig. 1). This results in dielectrophoretic forces that may attract charged molecules from the cytosol and compromise normal cytokinesis.7”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [7]
The inhibitory effect of TTFields increases with increasing electric field intensity, resulting in complete proliferation arrest of rat glioma cells after 24 h exposure to a field intensity of 2.25 V/cm.
“the inhibitory effect increases with an increasing electric field intensity, resulting in a complete proliferation arrest of rat glioma cells after 24 h exposure to a field intensity of 2.25 V/cm.”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
Treated cells remain stationary at metaphase for several hours, accompanied by abnormal mitotic figures as well as membrane rupture and blebbing leading to apoptosis.
“A significant prolongation of mitosis was predicted, where treated cells remain stationary at metaphase for several hours, which was accompanied by abnormal mitotic figures as well as membrane rupture and blebbing leading to apoptosis [2,3].”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
Low-intensity (1-3 V/cm), intermediate frequency (100-300 kHz) electric fields have a profoundly inhibitory effect on the growth rate of various mammalian tumor cell lines.
“Kirson et al. [2] reported the discovery that low-intensity (1–3 V/cm), intermediate frequency (100–300 kHz) electric fields have a profoundly inhibitory effect on the growth rate of various mammalian tumor cell lines [2,3,4].”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
The optimal frequency for the inhibitory effect of TTFields is inversely related to cell size.
“the optimal frequency for the inhibitory effect of TTFields is inversely related to cell size [2,44]”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
Cytoplasmic organelles can move at velocities up to 30 μm/s and could pile up at the cleavage furrow within a few minutes, interfering with cytokinesis and potentially leading to cell destruction.
“These organelles can move at velocities up to 30 μm/s and, as a result, they could pile up at the cleavage furrow within a few minutes, interfering with cytokinesis, which may lead to cell destruction.”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
TTField-generated forces on cytoplasmic organelles may reach up to 60 pN, causing their movement toward the cleavage furrow.
“As a consequence, the TTField-generated forces acting on these organelles may reach values up to 60 pN resulting in their movement toward the cleavage furrow.”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
Cytoplasmic organelles are electrically polarized by TTFields within dividing cells.
“It was determined that cytoplasmic organelles are electrically polarized by the field within dividing cells.”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
Septin has been found affected by TTFields.
“Another potential member of the cytoskeleton that has been found affected by TTFields [2] is the protein called septin”
From An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields (2016) · cites this paper as [2]
100 kHz to 1 MHz alternating electric fields have significant specific effects on dividing cells.
“we have recently demonstrated (9) that 100 KHz to 1 MHz ac fields have significant specific effects on dividing cells.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
Low intensity, intermediate frequency electric fields inhibit cancerous cell growth in vitro by an anti-microtubule mechanism of action.
“We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
The effects of TTFields during cytokinesis are based on unidirectional forces induced by inhomogeneous fields at the bridge separating daughter cells, which interfere with spindle tubulin orientation and induce dielectrophoresis.
“The basis of these effects during cytokinesis was shown to be the unidirectional forces induced by the inhomogeneous fields at the bridge separating the daughter cells (Fig. 1B) that interfere with spindle tubulin orientation and induce dielectrophoresis.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
TTFields applied by implanted electrodes inhibit the growth of dermal tumors in mice.
“Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
The finding that two perpendicular fields are more effective is consistent with previously reported effects on malignant melanoma cells.
“This result is consistent with the previously reported effects on malignant melanoma cells (9).”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
The TTFields described in ref. 9 are an exception to the presumed lack of effect of intermediate frequency fields.
“An exception, are the TTFields described in ref. 9.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
The in vivo frequency dependence of B16F1 melanoma shows the same frequency dependency as cultured B16F1 cells, supporting the conclusion that 100 kHz is the optimum frequency.
“it shows the same frequency dependency as the dependence of cultured B16F1 cells reported in ref. 9, which supports the conclusion that this is the optimum frequency.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
The tumor inhibitory effect of TTFields has been attributed previously to two separate mechanisms: interference with the formation of the mitotic spindle microtubules and physical destruction of cells during cleavage, both of which are strongly dependant on the orientation of mitosis axis versus the field vectors.
“The tumor inhibitory effect of TTFields has been attributed previously to two separate mechanisms (9): interference with the formation of the mitotic spindle microtubules and physical destruction of cells during cleavage, both of which are strongly dependant on the orientation of mitosis axis versus the field vectors.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [9]
TTFields are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, leading to mitotic arrest and cell death.
“Tumor-treating fields (TTFields) are lowintensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death.”
TTFields have demonstrated effectiveness in the treatment of solid tumors in vitro and in vivo.
“TTFields have demonstrated effectiveness in the treatment of solid tumors in vitro and in vivo.[6][7][8][9][10]”
Treatment efficacy was positively correlated with TTFields intensities.
“Treatment efficacy was found to be positively correlated with TTFields intensities, as previously described (data not shown).6,7”
TTFields forces act on the dipole moment of tubulin chains, leading to misalignment of mitotic spindle filaments, and paclitaxel stabilizes the link between individual tubulin dimers, increasing the length and average dipole moment of tubulin filaments, which could increase TTFields-induced forces and sensitize cells to TTFields.
“TTFields forces act on the dipole moment of tubulin chains, leading to misalignment of mitotic spindle filaments 6 and paclitaxel stabilizes the link between individual tubulin dimers, subsequently increasing the length and average dipole moment of the tubulin filaments.This, in turn, could increase the TTFields-induced forces and sensitize cells to TTFields.”
The additive effect of TTFields and pemetrexed is possibly explained by pemetrexed acting on G1 and S phases and TTFields acting on M phase.
“This effect is possibly explained by the different stages of mitosis at which the two treatment modalities putatively operate: Pemetrexed inhibits three enzymes responsible for purine and pyrimidine synthesis, thereby acting on the G1 and S phases of the cell cycle, 16 and TTFields therapy predominantly acts on cells in the M phase.6,7,9”
TTFields disrupt cancer cell replication in vitro.
“TTFields are low intensity, intermediate frequency alternating electric fields that were shown to disrupt cancer cell replication in vitro and to slow tumor progression in animal cancer models and patients with recurrent and newly diagnosed glioblastoma [18–20].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [19]
TTFields slow tumor progression in animal cancer models and in patients with recurrent and newly diagnosed glioblastoma.
“TTFields are low intensity, intermediate frequency alternating electric fields that were shown to disrupt cancer cell replication in vitro and to slow tumor progression in animal cancer models and patients with recurrent and newly diagnosed glioblastoma [18–20].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [19]
A 0.5 V/cm field intensity measured in rabbit lungs is below the threshold required for cancerous cell growth inhibition.
“Such a 0.5 V/cm field intensity measured in the rabbit’ lungs is below the threshold required for cancerous cell growth inhibition [19].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [19]
Under cell culture conditions, TTFields forces affect cells during division, inducing violent plasma membrane contractions during mitosis and cell death.
“Specifically, under cell culture conditions, these forces affected cells during division in a way that resulted in the induction of violent plasma membrane contractions during mitosis and cell death [38, 43].”
From Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit (2015) · cites this paper as [38]
Alternating electric fields (TTFields) disrupt cells during mitosis within a narrow range of frequencies with peak activity between 100 and 200 kHz, while fields at 500 kHz or above have little measurable effect on cell biology.
“It has recently been demonstrated that alternating electric fields referred to here as Tumor Treating Fields (TTFields), are able to disrupt cells during mitosis within a narrow range of frequencies with peak activity between 100 and 200 kHz; such fields have little measureable effect on cell biology at frequencies of 500 kHz or above, [38].”
From Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit (2015) · cites this paper as [38]
TTFields-treated cultures show a small increase in mitotic cells at later time points relative to control cultures, demonstrating an increase in time in mitosis.
“Similar to other studies [38], we noted a small increase in mitotic cells at later time points in the TTFields-treated cultures relative to control cultures demonstrating an increase in time in mitosis.”
From Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit (2015) · cites this paper as [38]
Previous studies showed that cells exposed to TTFields exhibit violent plasma membrane contractions during mitosis, increased time in mitosis, and decreased cellular accumulation in exposed cultures.
“Previous studies showed that cells exposed to TTFields exhibited violent plasma membrane contractions during mitosis, increased time in mitosis and decreased cellular accumulation in exposed cultures [38].”
From Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit (2015) · cites this paper as [38]
Previous studies showed that TTFields perturbed cells in mitosis resulting in plasma membrane contractions and the formation of dynamic blebs on the cell surface.
“Previous studies showed that TTFields perturbed cells in mitosis resulting in plasma membrane contractions and the formation of dynamic blebs on the cell surface. [38, 43].”
From Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit (2015) · cites this paper as [38]
TTFields affect cellular physiology through their effects on proteins that possess high dipole moments and are critical to specific cellular functions, such as mitosis.
“TTFields are able to affect cellular physiology through their effects on proteins that both possess high dipole moments and are also critical to specific cellular functions, in this case mitosis [38].”
From Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit (2015) · cites this paper as [38]
TTFields have no effect on quiescent cells while having an anti-mitotic effect on dividing cells.
“These specially tuned fields have no effect on quiescent cells while having an anti-mitotic effect on dividing cells.”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [2]
TTFields have been demonstrated to be highly effective when applied to cell cultures, animal cancer models, and patients with locally advanced and/or metastatic solid tumors.
“A new physical cancer treatment modality termed Tumor Treating Fields, or TTFields, has recently been demonstrated to be highly effective when applied to cell cultures, animal cancer models, as well as to patients suffering from locally advanced and or metastatic solid tumors [1-3].”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [2]
In the specific case of paclitaxel, the combined effect may be attributed to their similar site of action - the spindle microtubules.
“In the specific case of Paclitaxel, one of the most commonly used treatments for late-stage human breast cancer [20], the combined effect may be attributed to their similar site of action – the spindle microtubules [1,2,21].”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [2]
One of the mechanisms of action of TTFields is the misalignment of mitotic spindle filaments as a result of TTFields forces on tubulin chains.
“One of the mechanisms of action of TTFields is the misalignment of mitotic spindle filaments as a result of TTFields forces on tubulin chains [2].”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [2]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Claimed normal mitosis duration conflicts with control measurements
MinorThe figure caption says normal mitosis lasts less than one hour, whereas the reported control mean is 62 minutes and the range extends to 78 minutes.
“Contrary to normal mitosis, the duration of which is less than 1 h”
“whereas under control conditions, average mitosis duration was 62 Ϯ 8 min from cell rounding to cytokinesis (mean Ϯ SD, n ϭ 12; range, 47-78 min).”
Human and animal cell-line counts are reversed
MinorThe listed cell lines comprise six human and five animal lines, but the figure caption reports seven human and four animal lines.
“These included human melanoma (Patricia), glioma (U-118, U-87), Lung (H-1299), prostate (PC3), and breast (MDA231) cancerous cell lines as well as mouse melanoma (B16F1), rat glioma (F-98, C-6, and RG2), and mouse adenocarcinoma (CT-26) cell lines”
“In all four animal cell lines (Ⅺ) and seven human cell lines (f) tested”
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- Authors
- Kirson, E. D., Gurvich, Z., Schneiderman, R., Dekel, E., Itzhaki, A., Wasserman, Y., Schatzberger, R., & Palti, Y.
- Affiliations
- 1Department of Biomedical Engineering, NovoCure Ltd., Haifa, Israel;
- Technion – Israel Institute of Technology (IL)
- Weizmann Institute of Science (IL)
- Elisha Hospital (IL)
- ORCID
- Palti, Yoram
- Venue
- Cancer research
- Published
- 2004-05-01
- Volume
- 64
- Issue
- 9
- Pages
- 3288-3295
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2098950184
- Semantic Scholar
- 57d3f1baa7124bd17ab9dd3344010122c2f2d644
- Cited by
- 827
- References
- 25
- Citations by year
- 2026: 45 · 2025: 57 · 2024: 66 · 2023: 88 · 2022: 87 · 2021: 52 · 2020: 63 · 2019: 46 · 2018: 56 · 2017: 44 · 2016: 50 · 2015: 34 · 2014: 33 · 2013: 24 · 2012: 23
- FWCI
- 1.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Magnetic and Electromagnetic Effects
- Keywords
- AC electric field, tumor cell growth inhibition, non-thermal effects, mitotic spindle disruption, cell division arrest, frequency dependence, tumor growth in mice, B16F1 melanoma cells, CT26 cells, tumor cell quiescence
- MeSH terms
- Animals, Cell Division, Electric Stimulation Therapy, Humans, Neoplasms, Cell Line, Tumor, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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