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Am J Cancer Res. 2019 Feb 1;9(2):378-389. eCollection 2019.

Epithelial ovarian cancer: feasibility of image-guided intratumoral radiofrequency hyperthermia-enhanced direct gene therapy.

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Image-Guided Biomolecular Intervention Research, Section of Interventional Radiology, Department of Radiology, University of Washington School of Medicine Seattle, WA, USA.
Department of Interventional Oncology, Renji Hospital, Sochool of Medicine, Shanghai Jiaotong University Shanghai, China.
Department of Radiology, Guizhou General Hospital Guiyang, China.
Department of Pathology, Overlake Medical Center and Incyte Diagnostics Bellevue, WA, USA.


The aim of this study was to develop an interventional oncologic technique, "Image-guided intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus-thymidine kinase (HSV-TK) gene therapy of ovarian cancer. This study consisted of three portions: (1) serial in-vitro experiments to establish "proof-of-principle" of this novel technique using human ovarian cancer cells; (2) serial in-vivo experiments to validate technical feasibility using animal models with the same orthotopic ovarian cancers; and (3) serial investigations into the underlying bio-molecular mechanisms of this technique. We included four subject groups: (i) combination therapy with RFH+HSV-TK gene therapy; (ii) gene therapy-only; (iii) RFH-only; and (iv) Phosphate-buffered saline (PBS). For in-vitro experiments, confocal microscopy and MTS assays were performed to quantify HSV-TK gene expression and assess cell viability. For in-vivo experiments, bioluminescence optical and ultrasound imaging were used to assess therapeutic effectiveness. These results were correlated with subsequent pathologic/laboratory studies to further elucidate the biologic mechanisms of this technique. In in-vitro experiments, combination therapy resulted in the lowest cell proliferation and greatest increase in HSV-TK gene expression among four subject groups. In in-vivo experiments, combination therapy lead to significant decreases of bioluminescence signals and sizes of tumors in combination therapy by optical and ultrasound imaging. Pathology/laboratory examinations confirmed the significantly increased expression of Bax, Caspase-3, HSP70, IL-2, and CD94 in cancer tissues subjected to combination therapy. "Image-guided intratumoral RFH-enhanced direct gene therapy" is an effective interventional oncologic technique which functions through apoptotic/anti-tumor immunity pathways. This technical development may open new avenues for treating ovarian cancer.


HSV-TK/GCV; Radiofrequency hyperthermia; gene therapy; molecular image; ovarian cancer


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