肿瘤治疗电场:恶性肿瘤治疗新领域
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摘要
近年来,随着分子靶向治疗和免疫治疗的突破性进展,恶性肿瘤的治疗发生了革命性变化,但其仍然是导致目前全球疾病死亡的主要原因。研究表明,肿瘤治疗电场(tumor treating fields,TTFields)对肿瘤生长具有良好的抑制作用,其由低强度(1～2 V/cm)、中频(100～200 kHz)交流电场构成,通过阻止肿瘤细胞有丝分裂纺锤体的形成和介电电泳致细胞结构紊乱和破坏来诱导分裂期细胞的凋亡,以期达到抗肿瘤治疗的目的,且效果明显、毒副作用小和潜力大。TTFields在多种肿瘤的发生发展过程中都发挥着重要作用,其为恶性肿瘤患者的治疗带来新的福音,本文就TTFields最新的研究进展进行综述。
In recent years, with the breakthrough of molecular targeted therapy and immunotherapy, the treatment of malignant tumor has undergone revolutionary changes, but it is still the main cause of global disease death. Research has shown that tumor treating fields(TTFields) has good inhibitory effect on tumor growth by low intensity(1-2 V/cm), intermediate frequency(100-200 kHz) ac electric field, which can prevent the formation of tumor cell mitotic spindle and dielectrophoresis cell structure disturbance and destruction to induce split phase of cell apoptosis, in order to achieve the purpose of anti-tumor treatment, and the effect is obvious, small side effects and potential. TTFields plays an important role in the occurrence and development of a variety of tumors, which brings new benefits to the treatment of patients with malignant tumors. This paper reviews the latest research progress of TTFields.
In recent years, with the breakthrough of molecular targeted therapy and immunotherapy, the treatment of malignant tumor has undergone revolutionary changes, but it is still the main cause of global disease death. Research has shown that tumor treating fields(TTFields) has good inhibitory effect on tumor growth by low intensity(1-2 V/cm), intermediate frequency(100-200 kHz) ac electric field, which can prevent the formation of tumor cell mitotic spindle and dielectrophoresis cell structure disturbance and destruction to induce split phase of cell apoptosis, in order to achieve the purpose of anti-tumor treatment, and the effect is obvious, small side effects and potential. TTFields plays an important role in the occurrence and development of a variety of tumors, which brings new benefits to the treatment of patients with malignant tumors. This paper reviews the latest research progress of TTFields.
引文
[1] SIEGEL RL, MILLER KD, JEMAL A, et al. Cancer statistics, 2019[J]. CA Cancer J Clin, 2019, 69(1):7-34.
[2] TAB CS, KUMARAKULASINGHE NB, HUANG YQ, et al. Third generation EGFR TKIs:current data and future directions[J]. Mol Cancer, 2018, 17(1):29.
[3] THAI AA, SOLOMON BJ. Treatment of ALK-positive nonsmall cell lung cancer:recent advances[J]. Curr Opin Oncol, 2018, 30(2):84-91.
[4] JIA L, ZHANG Q, ZHANG R. PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy[J].Cancer Biol Med, 2018, 15(2):116-123.
[5] ZHAO Y, YANG W, HUANG Y, et al. Evolving roles for targeting CTLA-4 in cancer immunotherapy[J]. Cell Physiol Biochem, 2018,47(2):721-734.
[6] KORSHOJ AR, LUKACOVA S, MIKIC N, et al. Tumor treating fields in cancer treatment in Denmark[J]. Ugeskr Laeger, 2019, 181(5):V07180481.
[7] GERA N, YANG A, HOLTZMAN TS, et al. Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit[J].PLoS One, 2015, 10(5):e0125269.
[8] HOTTINGER AF, PACHECO P, STUPP R. Tumor treating fields:a novel treatment modality and its use in brain tumors[J]. Neuro Oncol, 2016, 18(10):1338-1349.
[9] SWANSON KD, LOK E, WONG ET. An overview of alternating electric fields therapy(NovoTTF therapy)for the treatment of malignant glioma[J]. Curr Neurol Neurosci Rep, 2016, 16(1):8.
[10] MOSHE G, ROSA S SC, TALI V, et al. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells[J]. Sci Rep, 2015, 5:18046.
[11] ELIJAH J, MUN, HANI M, et al. Tumor-treating fields:a fourth modality in cancer treatment[J]. Clin Cancer Res, 2018, 24(2):266-275.
[12] BRANTER J, BASU S, SMITH S. Tumour treating fields in a combinational therapeutic approach[J]. Oncotarget, 2018, 9(93):36631-36644.
[13] WONG ET, LOK E, SWANSON KD. Alternating electric fields therapy for malignant gliomas:from bench observation to clinical reality[J]. Prog Neurol Surg, 2018, 32:180-195.
[14] KILLOCK D. CNS cancer:TTFields improve survival[J]. Nat Rev Clin Oncol, 2018, 15(3):136.
[15] PLESS M, DROEGE C, VON MOOS R, et al. A phaseⅠ/Ⅱtrial of combination with pemetrexed tumor treating fields therapy in for advanced non-small cell cancer[J]. Lung Cancer, 2013, 81(3):445-450.
[16] MUNSTER M, ROBERTS CP, SCHMEL EM, et al. Abstract 5365:Alternating electric fields(TTFields)in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo[J]. Cancer Research, 2015, 75(15 supplement):5365-5365.
[17] BENAVIDES M, GUILLEN C, RIVERA F, et al. Abstract CT130:PANOVA:a phaseⅡstudy of TTFields(150 kHz)concomitant with standard chemotherapy for front-line therapy of advanced pancreatic adenocarcinoma-updated efficacy results[J]. Cancer Res, 2017, 77(13 Suppl):CT130.
[18] ORNELAS AS, PORTER AB, SHARMA A, et al. What is the role of tumor-treating fields in newly diagnosed glioblastoma?[J].Neurologist, 2019, 24(2):71-73.
[19] MAGOULIOTIS DE, ASPRODINI EK, SVOKOS KA, et al.Tumor-treating fields as a fourth treating modality for glioblastoma:a meta-analysis[J]. Acta Neurochir(Wien), 2018, 160(6):1167-1174.
[20] ZHU JJ, DEMIREVA P, KANNER AA, et al. Health-related quality of life, cognitive screening, and functional status in a randomized phaseⅢtrial(EF-14)of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma[J]. J Neurooncol, 2017, 135(3):545-552.
[21] TAPHOORN MJB, DIRVEN L, KANNER AA, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma:a secondary analysis of a randomized clinical trial[J]. JAMA Oncol, 2018, 4(4):495-504.
[22] WENGER C, MIRANDA PC, SALVADOR R, et al. A review on tumor-treating fields(TTFields):clinical implications inferred from computational modeling[J]. IEEE Rev Biomed Eng, 2018, 11:195-207.
[23] LUKAS RV, RATERMANN KL, WONG ET, et al. Skin toxicities associated with tumor treating fields:case based review[J]. J Neurooncol, 2017, 135(3):593-599.
[24] BURRI SH, GONDI V, BROW PD, et al. The evolving role of tumor treating fields in managing glioblastoma:guide for oncologists[J].Am J Clin Oncol, 2018, 41(2):191-196.
[25] KINZEL A, AMBROGI M, VARSHAVER M, et al. Tumor treating fields for glioblastoma treatment:patient satisfaction and compliance with the second-generation Optune?system[J]. Clin Med Insights Oncol, 2019, 13:1179554918825449.
[26] ONKEN J, BARTELT F, VAJKOCZY P, et al. Acceptance and compliance of TTFields treatment among high grade glioma patients[J].J Neurooncol, 2018, 139(1):177-184.
[27] BENSON L. Tumor treating fields technology:alternating electric field therapy for the treatment of solid tumors[J]. Semin Oncol Nurs,2018, 34(2):137-150.
[28] ANTHONY P, MCARDLE S, MCHUGH M. Tumor treating fields:adjuvant treatment for high-grade gliomas[J]. Semin Oncol Nurs,2018, 34(5):454-464.
[29] ALMADANI A, SANJAY D, CHRIS RH, et al. Management of elderly patients with glioblastoma-multiforme-a systematic review[J]. Br J Radiol, 2018, 9:20170271.
[30] REITMAN ZJ, WINKLER F, ELIA AEH. New directions in the treatment of glioblastoma[J]. Semin Neurol, 2018, 38(1):50-61.
[31] WILLIAMS W. FDA approval for Novo TTF-100A system for recurrent glioblastoma[J]. Oncology Times, 2011, 33(9):20.
[32] SILGINER M, WELLER M, STUPP R, et al. Biological activity of tumor-treating fields in preclinical glioma models[J]. Cell Death Dis, 2017, 8(4):e2753.
[33] KESARI S, RAM Z. Tumor-treating fields plus chemotherapy versus chem-otherapy alone for glioblastoma at first recurrence:a post hoc analysis of the EF-14 trial[J]. CNS Oncol, 2017, 6(3):185-193.
[34] STUPP R, TAILLIBERT S, KANNER A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma:a randomized clinical trial[J]. JAMA, 2017, 318(23):2306-2316.
[35] TOMS SA, KIM CY, NICHOLAS G, et al. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma:a subgroup analysis of the EF-14phaseⅢtrial[J]. J Neurooncol, 2019, 141(2):467-473.
[36] GUZAUSKAS GF, SALZBERG M2, WANG BC. Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients[J]. CNS Oncol, 2018, 7(3):CNS23.
[37] BOSNYAK E, BARGER GR, MICHELHAUGH SK, et al. Amino acid PET imaging of the early metabolic response during tumor-treating fields(TTFields)therapy in recurrent glioblastoma[J]. Clin Nucl Med, 2018, 43(3):176-179.
[38] CASTELLVI Q, GINESTA MM, CAPELLA G, et al. Tumor growth delay by adjuvant alternating electric fields which appears non-thermally mediated[J]. Bioelectrochemistry, 2015, 105:16-24.
[39] RIVERA F, BENAVIDES M, GALLEGO J, et al. Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer:Results of the PANOVA phase 2 study[J].Pancreatology, 2019, 19(1):64-72.
[40] VERGOTEL I, MOOS Rv, MANSO L, et al. Tumor treating fields in combination with paclitaxel in recurrent ovarian carcinoma:results of the INNOVATE pilot study[J]. Gynecol Oncol, 2018, 150(3):471-477.
[41] NARASIMHA KUMAR K, KALAYARASAN S, LIANGHAO D, et al. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines[J]. Cell Death and Disease, 2017, 8:e2711.
[42] WEINBERG U, FARBER O, GILADI M, et al. 145TiPTTFields combined with PD-1 inhibitors or docetaxel for 2ndline treatment of non-small lung cancer(NSCLC):phase 3 LUNAR study[J]. Ann Oncol, 2017, 28(Suppl_2):mdx091. 065.
[43] GILADI M, MUNSTER M, BLAT R, et al. Abstract 5361:in vitro results and electric fields simulations suggest Tumor Treating Fields(TTFields)to be an effective treatment against Mesothelioma[J].Cancer Res, 2015, 75(15 Supplement):5361-5361.
[44] GROSSO F, MADRZAK J, CNNO L, et al. 215TiP:STELLAR-A phaseⅡtrial of TTFields with chemotherapy for first line treatment of malignant mesothelioma[J]. J Thorac Oncol, 2016, 11:S150.
[45] CHANG E, PATEL CB, POHLING C, et al. Tumor treating fields increases membrane permeability in glioblastoma cells[J]. Cell Death Discov, 2018, 4:113.
[46] KARANAM NK, SRINIVASAN K, DING L, et al. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines[J]. Cell Death Dis, 2017, 8(3):e2711.
[47] GILADI M, MUNSTER M, SCHNEIDERMAN RS, et al. Tumor treating fields(TTFields)delay DNA damage repair following radiation treatment of glioma cells[J]. Radiat Oncol, 2017, 12(1):206.
[48] KESSLER AF, FROMBLING GE, GROSS F, et al. Effects of tumor treating fields(TTFields)on glioblastoma cells are augmented by mitotic checkpoint inhibition[J]. Cell Death Discov, 2018, 4:12.
[49] JO Y, KIM EH, SAI S, et al. Functional biological activity of sorafenib as a tumor-treating field sensitizer for glioblastoma therapy[J]. Int J Mol Sci, 2018, 19(11):pii:E3684.
[50] NEUHAUS E, ZIRJACKS L, GANSER K, et al. Alternating electric fields(TTFields)activate Cav1.2 channels in human glioblastoma cells[J]. Cancers(Basel), 2019, 11(1):pii:E110.
[51] SHTEINGAUZ A, PORAT Y, VOLOSHIN T, et al. AMPK-dependent autophagy upregulation serves as a survival mechanism in response to tumor treating fields(TTFields)[J]. Cell Death Dis, 2018, 9(11):1074.
[2] TAB CS, KUMARAKULASINGHE NB, HUANG YQ, et al. Third generation EGFR TKIs:current data and future directions[J]. Mol Cancer, 2018, 17(1):29.
[3] THAI AA, SOLOMON BJ. Treatment of ALK-positive nonsmall cell lung cancer:recent advances[J]. Curr Opin Oncol, 2018, 30(2):84-91.
[4] JIA L, ZHANG Q, ZHANG R. PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy[J].Cancer Biol Med, 2018, 15(2):116-123.
[5] ZHAO Y, YANG W, HUANG Y, et al. Evolving roles for targeting CTLA-4 in cancer immunotherapy[J]. Cell Physiol Biochem, 2018,47(2):721-734.
[6] KORSHOJ AR, LUKACOVA S, MIKIC N, et al. Tumor treating fields in cancer treatment in Denmark[J]. Ugeskr Laeger, 2019, 181(5):V07180481.
[7] GERA N, YANG A, HOLTZMAN TS, et al. Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit[J].PLoS One, 2015, 10(5):e0125269.
[8] HOTTINGER AF, PACHECO P, STUPP R. Tumor treating fields:a novel treatment modality and its use in brain tumors[J]. Neuro Oncol, 2016, 18(10):1338-1349.
[9] SWANSON KD, LOK E, WONG ET. An overview of alternating electric fields therapy(NovoTTF therapy)for the treatment of malignant glioma[J]. Curr Neurol Neurosci Rep, 2016, 16(1):8.
[10] MOSHE G, ROSA S SC, TALI V, et al. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells[J]. Sci Rep, 2015, 5:18046.
[11] ELIJAH J, MUN, HANI M, et al. Tumor-treating fields:a fourth modality in cancer treatment[J]. Clin Cancer Res, 2018, 24(2):266-275.
[12] BRANTER J, BASU S, SMITH S. Tumour treating fields in a combinational therapeutic approach[J]. Oncotarget, 2018, 9(93):36631-36644.
[13] WONG ET, LOK E, SWANSON KD. Alternating electric fields therapy for malignant gliomas:from bench observation to clinical reality[J]. Prog Neurol Surg, 2018, 32:180-195.
[14] KILLOCK D. CNS cancer:TTFields improve survival[J]. Nat Rev Clin Oncol, 2018, 15(3):136.
[15] PLESS M, DROEGE C, VON MOOS R, et al. A phaseⅠ/Ⅱtrial of combination with pemetrexed tumor treating fields therapy in for advanced non-small cell cancer[J]. Lung Cancer, 2013, 81(3):445-450.
[16] MUNSTER M, ROBERTS CP, SCHMEL EM, et al. Abstract 5365:Alternating electric fields(TTFields)in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo[J]. Cancer Research, 2015, 75(15 supplement):5365-5365.
[17] BENAVIDES M, GUILLEN C, RIVERA F, et al. Abstract CT130:PANOVA:a phaseⅡstudy of TTFields(150 kHz)concomitant with standard chemotherapy for front-line therapy of advanced pancreatic adenocarcinoma-updated efficacy results[J]. Cancer Res, 2017, 77(13 Suppl):CT130.
[18] ORNELAS AS, PORTER AB, SHARMA A, et al. What is the role of tumor-treating fields in newly diagnosed glioblastoma?[J].Neurologist, 2019, 24(2):71-73.
[19] MAGOULIOTIS DE, ASPRODINI EK, SVOKOS KA, et al.Tumor-treating fields as a fourth treating modality for glioblastoma:a meta-analysis[J]. Acta Neurochir(Wien), 2018, 160(6):1167-1174.
[20] ZHU JJ, DEMIREVA P, KANNER AA, et al. Health-related quality of life, cognitive screening, and functional status in a randomized phaseⅢtrial(EF-14)of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma[J]. J Neurooncol, 2017, 135(3):545-552.
[21] TAPHOORN MJB, DIRVEN L, KANNER AA, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma:a secondary analysis of a randomized clinical trial[J]. JAMA Oncol, 2018, 4(4):495-504.
[22] WENGER C, MIRANDA PC, SALVADOR R, et al. A review on tumor-treating fields(TTFields):clinical implications inferred from computational modeling[J]. IEEE Rev Biomed Eng, 2018, 11:195-207.
[23] LUKAS RV, RATERMANN KL, WONG ET, et al. Skin toxicities associated with tumor treating fields:case based review[J]. J Neurooncol, 2017, 135(3):593-599.
[24] BURRI SH, GONDI V, BROW PD, et al. The evolving role of tumor treating fields in managing glioblastoma:guide for oncologists[J].Am J Clin Oncol, 2018, 41(2):191-196.
[25] KINZEL A, AMBROGI M, VARSHAVER M, et al. Tumor treating fields for glioblastoma treatment:patient satisfaction and compliance with the second-generation Optune?system[J]. Clin Med Insights Oncol, 2019, 13:1179554918825449.
[26] ONKEN J, BARTELT F, VAJKOCZY P, et al. Acceptance and compliance of TTFields treatment among high grade glioma patients[J].J Neurooncol, 2018, 139(1):177-184.
[27] BENSON L. Tumor treating fields technology:alternating electric field therapy for the treatment of solid tumors[J]. Semin Oncol Nurs,2018, 34(2):137-150.
[28] ANTHONY P, MCARDLE S, MCHUGH M. Tumor treating fields:adjuvant treatment for high-grade gliomas[J]. Semin Oncol Nurs,2018, 34(5):454-464.
[29] ALMADANI A, SANJAY D, CHRIS RH, et al. Management of elderly patients with glioblastoma-multiforme-a systematic review[J]. Br J Radiol, 2018, 9:20170271.
[30] REITMAN ZJ, WINKLER F, ELIA AEH. New directions in the treatment of glioblastoma[J]. Semin Neurol, 2018, 38(1):50-61.
[31] WILLIAMS W. FDA approval for Novo TTF-100A system for recurrent glioblastoma[J]. Oncology Times, 2011, 33(9):20.
[32] SILGINER M, WELLER M, STUPP R, et al. Biological activity of tumor-treating fields in preclinical glioma models[J]. Cell Death Dis, 2017, 8(4):e2753.
[33] KESARI S, RAM Z. Tumor-treating fields plus chemotherapy versus chem-otherapy alone for glioblastoma at first recurrence:a post hoc analysis of the EF-14 trial[J]. CNS Oncol, 2017, 6(3):185-193.
[34] STUPP R, TAILLIBERT S, KANNER A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma:a randomized clinical trial[J]. JAMA, 2017, 318(23):2306-2316.
[35] TOMS SA, KIM CY, NICHOLAS G, et al. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma:a subgroup analysis of the EF-14phaseⅢtrial[J]. J Neurooncol, 2019, 141(2):467-473.
[36] GUZAUSKAS GF, SALZBERG M2, WANG BC. Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients[J]. CNS Oncol, 2018, 7(3):CNS23.
[37] BOSNYAK E, BARGER GR, MICHELHAUGH SK, et al. Amino acid PET imaging of the early metabolic response during tumor-treating fields(TTFields)therapy in recurrent glioblastoma[J]. Clin Nucl Med, 2018, 43(3):176-179.
[38] CASTELLVI Q, GINESTA MM, CAPELLA G, et al. Tumor growth delay by adjuvant alternating electric fields which appears non-thermally mediated[J]. Bioelectrochemistry, 2015, 105:16-24.
[39] RIVERA F, BENAVIDES M, GALLEGO J, et al. Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer:Results of the PANOVA phase 2 study[J].Pancreatology, 2019, 19(1):64-72.
[40] VERGOTEL I, MOOS Rv, MANSO L, et al. Tumor treating fields in combination with paclitaxel in recurrent ovarian carcinoma:results of the INNOVATE pilot study[J]. Gynecol Oncol, 2018, 150(3):471-477.
[41] NARASIMHA KUMAR K, KALAYARASAN S, LIANGHAO D, et al. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines[J]. Cell Death and Disease, 2017, 8:e2711.
[42] WEINBERG U, FARBER O, GILADI M, et al. 145TiPTTFields combined with PD-1 inhibitors or docetaxel for 2ndline treatment of non-small lung cancer(NSCLC):phase 3 LUNAR study[J]. Ann Oncol, 2017, 28(Suppl_2):mdx091. 065.
[43] GILADI M, MUNSTER M, BLAT R, et al. Abstract 5361:in vitro results and electric fields simulations suggest Tumor Treating Fields(TTFields)to be an effective treatment against Mesothelioma[J].Cancer Res, 2015, 75(15 Supplement):5361-5361.
[44] GROSSO F, MADRZAK J, CNNO L, et al. 215TiP:STELLAR-A phaseⅡtrial of TTFields with chemotherapy for first line treatment of malignant mesothelioma[J]. J Thorac Oncol, 2016, 11:S150.
[45] CHANG E, PATEL CB, POHLING C, et al. Tumor treating fields increases membrane permeability in glioblastoma cells[J]. Cell Death Discov, 2018, 4:113.
[46] KARANAM NK, SRINIVASAN K, DING L, et al. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines[J]. Cell Death Dis, 2017, 8(3):e2711.
[47] GILADI M, MUNSTER M, SCHNEIDERMAN RS, et al. Tumor treating fields(TTFields)delay DNA damage repair following radiation treatment of glioma cells[J]. Radiat Oncol, 2017, 12(1):206.
[48] KESSLER AF, FROMBLING GE, GROSS F, et al. Effects of tumor treating fields(TTFields)on glioblastoma cells are augmented by mitotic checkpoint inhibition[J]. Cell Death Discov, 2018, 4:12.
[49] JO Y, KIM EH, SAI S, et al. Functional biological activity of sorafenib as a tumor-treating field sensitizer for glioblastoma therapy[J]. Int J Mol Sci, 2018, 19(11):pii:E3684.
[50] NEUHAUS E, ZIRJACKS L, GANSER K, et al. Alternating electric fields(TTFields)activate Cav1.2 channels in human glioblastoma cells[J]. Cancers(Basel), 2019, 11(1):pii:E110.
[51] SHTEINGAUZ A, PORAT Y, VOLOSHIN T, et al. AMPK-dependent autophagy upregulation serves as a survival mechanism in response to tumor treating fields(TTFields)[J]. Cell Death Dis, 2018, 9(11):1074.