Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

被引:115
作者
Giladi, Moshe [1 ]
Munster, Mijal [1 ]
Schneiderman, Rosa S. [1 ]
Voloshin, Tali [1 ]
Porat, Yaara [1 ]
Blat, Roni [1 ]
Zielinska-Chomej, Katarzyna [2 ]
Haag, Petra [2 ]
Bomzon, Ze'ev [1 ]
Kirson, Eilon D. [1 ]
Weinberg, Uri [1 ]
Viktorsson, Kristina [2 ]
Lewensohn, Rolf [2 ]
Palti, Yoram [1 ]
机构
[1] Novocure Ltd, IL-31905 Haifa, Israel
[2] Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden
关键词
TTFields; Radiation treatment; Glioma; Radiosensitization; DNA damage repair; ALTERNATING ELECTRIC-FIELDS; RANDOMIZED PHASE-III; ADJUVANT TEMOZOLOMIDE; STRAND BREAKS; GLIOBLASTOMA; RADIOTHERAPY; CHEMOTHERAPY; PATHWAY; CANCER; CHEMORADIATION;
D O I
10.1186/s13014-017-0941-6
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity. Methods: The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing gamma H2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy). Results: TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation-or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the "skin sparing effect". Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions. Conclusions: Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models
引用
收藏
页数:13
相关论文
共 30 条
[1]  
Agarwala S S, 2000, Oncologist, V5, P144, DOI 10.1634/theoncologist.5-2-144
[2]   Glioma stem cells promote radioresistance by preferential activation of the DNA damage response [J].
Bao, Shideng ;
Wu, Qiulian ;
McLendon, Roger E. ;
Hao, Yueling ;
Shi, Qing ;
Hjelmeland, Anita B. ;
Dewhirst, Mark W. ;
Bigner, Darell D. ;
Rich, Jeremy N. .
NATURE, 2006, 444 (7120) :756-760
[3]   New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells [J].
Burdak-Rothkamm, Susanne ;
Prise, Kevin M. .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2009, 625 (1-3) :151-155
[4]  
CAPRANICO G, 1987, CANCER RES, V47, P3752
[5]   DNA strand breaks and apoptosis induced by oxaliplatin in cancer cells [J].
Faivre, S ;
Chan, D ;
Salinas, R ;
Woynarowska, B ;
Woynarowski, JM .
BIOCHEMICAL PHARMACOLOGY, 2003, 66 (02) :225-237
[6]   Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit [J].
Gera, Nidhi ;
Yang, Aaron ;
Holtzman, Talia S. ;
Lee, Sze Xian ;
Wong, Eric T. ;
Swanson, Kenneth D. .
PLOS ONE, 2015, 10 (05)
[7]   Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo [J].
Giladi, Moshe ;
Weinberg, Uri ;
Schneiderman, Rosa S. ;
Porat, Yaara ;
Munster, Michal ;
Voloshin, Tali ;
Blatt, Roni ;
Cahal, Shay ;
Itzhaki, Aviran ;
Onn, Amir ;
Kirson, Elon D. ;
Palti, Yoram .
SEMINARS IN ONCOLOGY, 2014, 41 :S35-S41
[8]   A MAMMALIAN-CELL CYCLE CHECKPOINT PATHWAY UTILIZING P53 AND GADD45 IS DEFECTIVE IN ATAXIA-TELANGIECTASIA [J].
KASTAN, MB ;
ZHAN, QM ;
ELDEIRY, WS ;
CARRIER, F ;
JACKS, T ;
WALSH, WV ;
PLUNKETT, BS ;
VOGELSTEIN, B ;
FORNACE, AJ .
CELL, 1992, 71 (04) :587-597
[9]  
Kim EH, 2016, ONCOTARGET
[10]   Disruption of cancer cell replication by alternating electric fields [J].
Kirson, ED ;
Gurvich, Z ;
Schneiderman, R ;
Dekel, E ;
Itzhaki, A ;
Wasserman, Y ;
Schatzberger, R ;
Palti, Y .
CANCER RESEARCH, 2004, 64 (09) :3288-3295