Non-Small-Cell Lung Cancer: Feasibility of Intratumoral Radiofrequency Hyperthermia-enhanced Herpes Simplex Virus Thymidine Kinase Gene Therapy.

Abstract

Purpose To validate the feasibility and efficacy of intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus (HSV) thymidine kinase (TK) and ganciclovir (GCV) (hereafter, HSV-TK/GCV) gene therapy for non-small-cell lung cancer (NSCLC). Materials and Methods This study was performed from November 11, 2015, to April 14, 2017, and included (a) in vitro experiments with human NSCLC cells to establish the proof of principle, (b) in vivo experiments using mice with subcutaneous NSCLC to further demonstrate the principle, and (c) in vivo experiments using rats with orthotopic NSCLC to validate the technical feasibility. Cells, nude mice, and nude rats were randomly divided into four groups (six animals per group): (a) combination therapy (HSV-TK/GCV combined with RFH), (b) RFH, (c) HSV-TK/GCV, and (d) phosphate-buffered saline. Data were analyzed by using the Dunnett t test or Kruskal-Wallis test. Results For in vitro experiments, the cell proliferation assay showed significantly diminished viable cells with combination therapy (mean, 0.56; 95% confidence interval [CI]: 0.44, 0.68) versus RFH (mean, 0.89; 95% CI: 0.82, 0.97), HSV-TK/GCV (mean, 0.71; 95% CI: 0.56, 0.86), and phosphate-buffered saline (mean, 1; 95% CI: 1, 1) (P < .05 for all). For in vivo experiments, optical imaging showed significantly decreased relative bioluminescence signal with combination therapy (mean, 0.71 [95% CI: 0.03, 1.39] in mice; 1.29 [95% CI: 0.51, 2.06] in rats) compared with RFH (mean, 2.66 [95% CI: 1.73, 3.59] in mice; 2.26 [95% CI: 1.51, 3.01] in rats), HSV-TK/GCV (mean, 1.37 [95% CI: 0.65, 2.08] in mice; 1.76 [95% CI: 1.20, 2.31] in rats), and phosphate-buffered saline (mean, 3.07 [95% CI: 2.50, 3.65] in mice; 2.94 [95% CI: 2.29, 3.58] in rats) (P < .001 for all). US showed that the smallest relative tumor volumes occurred with combination therapy (mean, 0.60; 95% CI: 0.15, 1.05) versus RFH (mean, 2.43; 95% CI: 1.80, 3.06), HSV-TK/GCV (mean, 1.32; 95% CI: 0.75, 1.89), and phosphate-buffered saline (mean, 2.56; 95% CI: 1.75, 3.38) (P < .05 for all) in the mouse subcutaneous model. Conclusion Intratumoral radiofrequency hyperthermia-enhanced herpes simplex virus thymidine kinase and ganciclovir gene therapy for non-small-cell lung cancer is feasible and can be guided by molecular imaging. © RSNA, 2018.

• Authors: Jiansong Ji, Qiaoyou Weng, Feng Zhang, Fu Xiong, Yin Jin, Junguo Hui, Jingjing Song, Jun Gao, Minjiang Chen, Qiang Li, David Shin, Xiaoming Yang
• Journal: Radiology (Radiology) Vol. 288 Issue 2 Pg. 612-620 (08 2018) ISSN: 1527-1315 [Electronic] United States
• PMID: 29893649 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Thymidine Kinase
• Ganciclovir

Topics

• Animals
• Antiviral Agents (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (therapy)
• Feasibility Studies
• Female
• Ganciclovir (therapeutic use)
• Genetic Therapy (methods)
• Humans
• Hyperthermia, Induced (methods)
• In Vitro Techniques
• Lung Neoplasms (therapy)
• Mice
• Mice, Nude
• Molecular Imaging
• Rats
• Rats, Nude
• Reproducibility of Results
• Simplexvirus (enzymology)
• Thymidine Kinase (genetics)
• Treatment Outcome
• Tumor Cells, Cultured