Selective toxicity of tumor treating fields to melanoma: an in vitro and in vivo study

Jo, Yunhui; Hwang, Sang‐Gu; Jin, Yeung Bae; Sung, Jaeyoung; Jeong, Youn Kyoung; Baek, Jong‐Min; Cho, Jae Min; Kim, Eun Ho; Yoon, Myonggeun

doi:10.1038/s41420-018-0106-x

Cited by 26 publications

(35 citation statements)

References 24 publications

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“…[2][3][4] Furthermore, by adapting the frequency and field intensity to the presumed size and physical properties of dividing tumor cells, nondividing normal cells are spared. 1,5,6 Preclinical studies have shown additive to synergistic effects when TTFields were used in combination with several classes of chemotherapeutic drugs, such as paclitaxel, cisplatin, pemetrexed, gemcitabine, doxorubicin, 5-FU (Fluorouracil), cyclophosphamide, DTIC (Dacarbazine), Irinotecan, and spindle assembly checkpoint inhibitors. [7][8][9][10][11][12] TTFields also target the calcium channel Cav1.2, and combinations of calcium antagonists, such as benidipine enhance glioma cell killing.…”

Section: Translational Significancementioning

confidence: 99%

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

Karanam

Ding

Asaithamby

et al. 2020

Translational Research

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Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM10 and the Fanconi's Anemia pathway genes. When markers of DNA replication stress as a result of TTFields exposure were examined, newly replicated DNA length was reduced with TTFields exposure time and there was increased R-loop formation. Furthermore, as cells were exposed to TTFields a conditional vulnerability environment developed which rendered cells more susceptible to DNA damaging agents or agents that interfere with DNA repair or replication fork maintenance. The effect of TTFields exposure with concomitant exposure to cisplatin or PARP inhibition, the combination of TTFields plus concomitant PARP inhibition followed by radiation, or radiation alone at the end of a TTFields exposure were all synergistic. Finally, gene expression analysis of 47 key mitosis regulator genes suggested that TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another, are likely initiated independently of one another. This suggests that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications. (Translational Research 2020; 217:33À46) Abbreviations: CI = combination index; DDR = DNA damage response; DSBs = double strand breaks; FA = Fanconi Anemia; GBM = glioblastoma; HSA = highest single agent; IR = ionizing radiation; NSCLC = nonÀsmall-cell lung cancer; RPA = replication protein A; TTFields = tumor treating fields

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Section: Translational Significancementioning

confidence: 99%

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

Karanam

Ding

Asaithamby

et al. 2020

Translational Research

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“…All rats in placebo (NIT) group were also exposed to non-contact electric fields in the same period, 3 weeks after the last corn oil administration. The duration of electric fields exposure for 10 hours per day was shorter than the previous exposure in our preliminary study 11 to minimize any possible side effects due to exposure to electric fields 8,10 . After treatment, all animals were returned to their communal cages.…”

Section: Experimental Designmentioning

confidence: 99%

“…Since skin toxicity or dermatitis arises in electric field therapy due to prolonged direct contact between the electrodes and the skin 10 , we have developed a type of non-contact electric field therapy using capacitive modality to avoid such injuries. In our previous study in preclinical setting, cancer therapy namely Electro-Capacitive Cancer Therapy (ECCT) using the non-contact electric fields with intermediate frequency (100 kHz) and low intensity (18 peak-to-peak Voltage/Vpp) could reduce the size of breast tumors in mice significantly without causing histological damage to mammary and skin tissues.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T cells response with decreased CD4/CD8 ratio during mammary tumors inhibition in rats induced by non-contact electric fields

Alamsyah¹,

Pratiwi

Firdausi

et al. 2021

F1000Res

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Background: Breast cancer is the most common cancer in women worldwide and is the leading cause of death in women with cancer. One novel therapy used for breast cancer treatment is non-contact electric fields called electro-capacitive cancer therapy (ECCT) with intermediate frequency (100 kHz) and low intensity (18 Vpp). The objective of this study was to examine the effect of ECCT on mammary tumors growth in rats and observing the immune responses that play a role in fighting the tumor. Methods: Female SD rats were used and divided into four groups, namely control (NINT), placebo (NIT), non- therapy (INT), and therapy (IT) groups with 6 biological replicates in each group. Rats in INT and IT groups were treated with 7,12-dimethylbenz[a]anthracene for mammary tumor induction. Only rats in NIT and IT groups were exposed to ECCT individually for 10 hours per day for 21 days. The size of all tumors was measured with a digital caliper. The distributions of PCNA, ErbB2, caspase-3, CD68, CD4 and CD8-positive cells were observed with immunohistochemistry and scoring with ImageJ. Results: The growth rate of mammary tumors in IT group was significantly lower (p<0.05) than that in the INT group. The number of mitotic figures and the percentage of PCNA, caspase-3, and CD68- positive cells in IT group were significantly lower (p<0.05) than those in INT group. Conversely, the percentage of CD8-positive T cells in IT group was significantly higher (p<0.05) than that in INT group. Moreover, the CD4/CD8 ratio in IT group was decreased. Some tumor tissues were blackened and detached from the surrounding tissue, resulting in an open wound which then healed up upon exposure. Conclusions: Non-contact electric fields exposure showed inhibition on mammary tumor growth in rats while inducing CD8+ T cells that lead to tumor cells death and potentially helps wound healing.

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“…Skin toxicity or dermatitis arises in electric field therapy due to prolonged direct contact between the electrodes and the skin 10 . As such, we have developed a type of non-contact electric field therapy using capacitive modality to avoid such injuries.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T cells response with decreased CD4/CD8 ratio during mammary tumors inhibition in rats induced by non-contact electric fields

Alamsyah¹,

Pratiwi

Firdausi

et al. 2021

F1000Res

View full text Add to dashboard Cite

Background: Breast cancer is the most common cancer in women worldwide and is the leading cause of death amongst women with cancer. One novel therapy used for breast cancer treatment constitutes non-contact electric fields and is called electro-capacitive cancer therapy (ECCT) with intermediate frequency and low intensity. The objective of this study was to examine the effect of ECCT on mammary tumors growth in rats and observing the immune responses that play a role in fighting the tumor. Methods: Female SD rats were used and divided into four groups, namely control (NINT), placebo (NIT), non- therapy (INT), and therapy (IT) groups with 6 biological replicates in each group. Rats in INT and IT groups were treated with 7,12-dimethylbenz[a]anthracene for mammary tumor induction. Only rats in NIT and IT groups were exposed to ECCT individually for 10 hours per day for 21 days. The size of all tumors was measured with a digital caliper. The distributions of PCNA, ErbB2, caspase-3, CD68, CD4, and CD8-positive cells were observed with immunohistochemistry and scoring with ImageJ. Results: The growth rate of mammary tumors in IT group was significantly lower (p<0.05) than that in INT group. The number of mitotic figures and the percentage of PCNA, caspase-3, and CD68-positive cells in IT group were significantly lower (p<0.05) than those in INT group. Conversely, the percentage of CD8-positive T cells in IT group was significantly higher (p<0.05) than that in INT group. Moreover, the CD4/CD8 ratio in IT group was found to have decreased. Some tumor tissues were blackened and detached from the surrounding tissue, resulting in an open wound which then healed upon exposure. Conclusions: Non-contact electric fields exposure showed inhibition on mammary tumor growth in rats while inducing CD8+ T cells, leading to tumor cell death and potentially helping wounds heal.

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Selective toxicity of tumor treating fields to melanoma: an in vitro and in vivo study

Cited by 26 publications

References 24 publications

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

Cytotoxic T cells response with decreased CD4/CD8 ratio during mammary tumors inhibition in rats induced by non-contact electric fields

Cytotoxic T cells response with decreased CD4/CD8 ratio during mammary tumors inhibition in rats induced by non-contact electric fields

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