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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.

Author information

1
Image-Guided Biomolecular Intervention Research, Section of Interventional Radiology, Department of Radiology, University of Washington School of Medicine Seattle, WA, USA.
2
Department of Interventional Oncology, Renji Hospital, Sochool of Medicine, Shanghai Jiaotong University Shanghai, China.
3
Department of Radiology, Guizhou General Hospital Guiyang, China.
4
Department of Pathology, Overlake Medical Center and Incyte Diagnostics Bellevue, WA, USA.

Abstract

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.

KEYWORDS:

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

PMID:
30906635
PMCID:
PMC6405963

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