Medical/biological study (experimental study)

Cancer cell proliferation is inhibited by specific modulation frequencies med./bio.

By: Zimmerman JW, Pennison MJ, Brezovich I, Yi N, Yang CT, Ramaker R, Absher D, Myers RM, Kuster N, Costa FP, Barbault A, Pasche B

Published in: Br J Cancer 2012; 106 (2): 307-313

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Aim of study (acc. to editor)

To study the effects of amplitude modulated electromagnetic fields on the cell proliferation of cancer cells. The authors aimed to investigate the mechanism of action of amplitude modulated electromagnetic fields used in previous clinical studies for the treatment of cancer patients (Barbault et la. 2009 and Costa et la. 2011).

Background/further details

There is clinical evidence that very low levels of amplitude modulated electromagnetic fields administered via an intrabuccal spoon-shaped probe may elicit therapeutic responses in patients with cancer. To understand the mechanism of this approach, hepatocellular carcinoma cells were exposed to 27.12 MHz radiofrequency electromagnetic fields to replicate the in vivo conditions. Additionally, cancer cells were exposed to tumour-specific modulation frequencies, previously identified by "biofeedback" methods in patients with a diagnosis of cancer (Barbault et la. 2009). Using such a patient-based "biofeedback" approach, Barbault et la. 2009 identified strikingly similar frequencies among patients with the same type of cancer and observed that patients with a different type of cancer had "biofeedback" responses to different frequencies.
Control modulation frequencies consisted of randomly chosen modulation frequencies.
Two different in vitro exposure systems were used to expose cells in culture (parallel plate capacitor and TEM cell).

Endpoint

cell viability/cell division/proliferation: cell proliferation of cancer cells

Exposure

- 410.231 Hz–27.12 MHz
- intermediate frequency
- RF
- AM amplitude modulation

Exposure	Parameters
Exposure 1: 27.12 MHz Modulation type: AM Exposure duration: continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days hepatocellular carcinoma-specific modulation frequencies	SAR: 0.03 W/kg (average at the monolayer) SAR: 0.05 W/kg (for additional experiments) SAR: 0.1 W/kg (for additional experiments) SAR: 1 W/kg (for additional experiments)
Exposure 2: 27.12 MHz Modulation type: AM Exposure duration: continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days randomly chosen frequencies	SAR: 0.03 W/kg (average at the monolayer) SAR: 0.05 W/kg (for additional experiments) SAR: 0.1 W/kg (for additional experiments) SAR: 1 W/kg (for additional experiments)
Exposure 3: 27.12 MHz Modulation type: AM Exposure duration: continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days breast tumor-specific modulation frequencies	SAR: 0.03 W/kg (average at the monolayer) SAR: 0.05 W/kg (for additional experiments) SAR: 0.1 W/kg (for additional experiments) SAR: 1 W/kg (for additional experiments)
Exposure 4: 27.12 MHz Modulation type: AM Exposure duration: continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days	SAR: 0.4 W/kg

Exposure 1

Main characteristics

Frequency	27.12 MHz
Type	electromagnetic field
Waveform	sinusoidal
Exposure duration	continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days
Additional info	hepatocellular carcinoma-specific modulation frequencies

Modulation

Modulation type	AM
Modulation frequency	410.23 Hz–20.365284 kHz

Exposure setup

Exposure source	parallel plate capacitor
Setup	four 14 cm x 21 cm parallel plate capacitors each consisting of 3 brass plates connected via a coaxial cable to a signal generator and placed inside an incubator
Sham exposure	A sham exposure was conducted.

Parameters

Measurand	Value	Type	Method	Mass	Remarks
SAR	0.03 W/kg	-	-	-	average at the monolayer
SAR	0.05 W/kg	-	-	-	for additional experiments
SAR	0.1 W/kg	-	-	-	for additional experiments
SAR	1 W/kg	-	-	-	for additional experiments

Exposure 2

Main characteristics

Frequency	27.12 MHz
Type	electromagnetic field
Waveform	sinusoidal
Exposure duration	continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days
Additional info	randomly chosen frequencies

Modulation

Modulation type	AM
Modulation frequency	504.28 Hz–22.401812 kHz

Exposure setup

Exposure source	same setup as exposure 1
Sham exposure	A sham exposure was conducted.

Parameters

Measurand	Value	Type	Method	Mass	Remarks
SAR	0.03 W/kg	-	-	-	average at the monolayer
SAR	0.05 W/kg	-	-	-	for additional experiments
SAR	0.1 W/kg	-	-	-	for additional experiments
SAR	1 W/kg	-	-	-	for additional experiments

Exposure 3

Main characteristics

Frequency	27.12 MHz
Type	electromagnetic field
Waveform	sinusoidal
Exposure duration	continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days
Additional info	breast tumor-specific modulation frequencies

Modulation

Modulation type	AM
Modulation frequency	181.821 Hz–19.406211 kHz

Exposure setup

Exposure source	same setup as exposure 1
Sham exposure	A sham exposure was conducted.

Parameters

Measurand	Value	Type	Method	Mass	Remarks
SAR	0.03 W/kg	-	-	-	average at the monolayer
SAR	0.05 W/kg	-	-	-	for additional experiments
SAR	0.1 W/kg	-	-	-	for additional experiments
SAR	1 W/kg	-	-	-	for additional experiments

Exposure 4

Main characteristics

Frequency	27.12 MHz
Type	electromagnetic field
Waveform	sinusoidal
Exposure duration	continuous for 1 h/day, 3 h/day or 6 h/day for 7 days or 3 h/day for 3 days
Additional info	it is not specified clearly in the article whether the modulation frequencies from Exposure 1, 2 and 3 were used here also or not

Modulation

Modulation type	AM

Exposure setup

Exposure source	TEM cell
Setup	two TEM cells placed inside an incubator; 2 x 6 tissue culture dishes (à 35 mm) per TEM cell
Sham exposure	A sham exposure was conducted.

Parameters

Measurand	Value	Type	Method	Mass	Remarks
SAR	0.4 W/kg	-	-	-	-

Reference articles

Nikoloski N et al. (2005): Reevaluation and improved design of the TEM cell in vitro exposure unit for replication studies

Exposed system:

intact cell/cell culture
Hep G2 cells (hepatic transformed cell line) and Huh7 cells (hepatocellular carcinoma cells); THLE-2 cells (normal hepatocytes); MCF-7 (breast cancer cell line), MCF-10A (breast epithelial cell line); lymphoblastoid cell lines

Methods Endpoint/measurement parameters/methodology

genotoxicity/mutation: karyotype changes (mitotic spindle disruption; confocal microscopy)
molecular biosynthesis: general gene expression (RNA-seq); validation of PLP2 and XCL2 gene expression (Real-time PCR)
cell viability/cell division/proliferation: growth inhibition (via ³H-thymidine incorporation or determination of cell proliferation/cell viability (based on ATP quantitation; luminescent commercial assay))

Investigated system:

Time of investigation:

during exposure
after exposure

Main outcome of study (acc. to author)

The growth of hepatocellular carcinoma and breast cancer cells was significantly decreased by hepatocellular carcinoma- and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect cell proliferation of non-malignant hepatocytes or normal breast epithelial cells. Inhibition of hepatocellular carcinoma cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, hepatocellular carcinoma-specific modulation frequencies disrupted the mitotic spindle.
These data uncovered a novel mechanism controlling the growth of cancer cells at specific modulation frequencies without affecting normal tissues, which may have broad implications in oncology.

Study character:

medical/biological study
experimental study
full/main study

Comments on this article

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Barbault A et al. (2009): Amplitude-modulated electromagnetic fields for the treatment of cancer: Discovery of tumor-specific frequencies and assessment of a novel therapeutic approach
Kirson ED et al. (2009): Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs
Salzberg M et al. (2008): A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors
Kirson ED et al. (2007): Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors
Kirson ED et al. (2004): Disruption of cancer cell replication by alternating electric fields

Cancer cell proliferation is inhibited by specific modulation frequencies med./bio.

Aim of study (acc. to editor)

Background/further details

Endpoint

Exposure

Exposure 1

Main characteristics

Modulation

Exposure setup

Parameters

Exposure 2

Main characteristics

Modulation

Exposure setup

Parameters

Exposure 3

Main characteristics

Modulation

Exposure setup

Parameters

Exposure 4

Main characteristics

Modulation

Exposure setup

Parameters

Reference articles

Methods Endpoint/measurement parameters/methodology

Main outcome of study (acc. to author)

Comments on this article

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