Abstract
Objective To establish the technique of intratumoral combination therapy of radiofrequency hyperthermia (RFH) with herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy for rat ovarian cancers. Material and methods This study consisted of three parts: (1) in vitro experiments to establish the ‘proof of principal’ that combination of RFH and HSV-TK gene therapy has the synergistic effect on human ovarian cancer cells; (2) creation of bioluminescence imaging-detectable rat ovarian cancer model; and (3) in vivo experiments using this rat model to validate the technical feasibility of the combination therapy. Cells and nude rats were divided into four groups: (i) combination therapy (HSV-TK/GCV + RFH); (ii) RFH; (iii) HSV-TK/GCV; and (iv) phosphate-buffered saline (PBS). Data were analyzed using Dunnett t-test or Kruskal–Wallis test. Results Cell proliferation assay demonstrated significantly greater reduction in viable cells with the combination therapy [0.52 (0.43, 0.61)] compared to other treatments [RFH 0.90 (0.84, 0.96), HSV-TK/GCV 0.71 (0.53, 0.88), PBS 1 (1, 1); p < .05]. For 24 rat models with bioluminescence imaging-detectable orthotopic ovarian cancer (n = 6 per group), optical imaging demonstrated significantly decreased relative bioluminescence signal with the combination therapy [0.81 (0.52, 1.08)] compared to other treatments [RFH 3.60 (2.34, 4.86), HSV-TK/GCV 2.21 (1.71, 2.71), PBS 3.74 (3.19, 4.29); p < .001]. Ultrasound imaging demonstrated the smallest relative tumor volume with the combination therapy [0.78 (0.45, 1.11) versus 3.50 (2.67, 4.33), 2.10 (0.83, 3.37), 3.70 (1.79, 5.61); p < .05]. Conclusion The feasibility of intratumoral RFH-enhanced HSV-TK/GCV gene therapy was established on a unique rat model with molecular imaging-detectable orthotopic ovarian cancer.
Highlights
Ovarian cancer accounts for 2.5% of all malignancies in women and 5% of female cancer deaths [1]
The feasibility of intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus-thymidine kinase (HSV-TK)/GCV gene therapy was established on a unique rat model with molecular imaging-detectable orthotopic ovarian cancer
Confocal microscopy (Fig. 1a) and the time-to-green fluorescence protein (GFP) expression curve (Fig. 1b) showed that GFP expression reached its peak on day 5 after cells were transfected with lentiviral GFP/ HSV-TK gene
Summary
Ovarian cancer accounts for 2.5% of all malignancies in women and 5% of female cancer deaths [1]. In 2018, there were approximately 22,240 newly diagnosed cases of ovarian cancer and 14,070 ovarian cancer deaths in the United States, representing the most common cause of death due to gynecologic malignancy [1,2,3]. 75% of women with ovarian carcinoma present with stage III or IV disease without any chance of curative surgery [2]. A majority of women with advanced-stage ovarian cancer will relapse due to platinum-resistant or refractory cancer, with a median time to recurrence of 16 months [5]
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