Radiofrequencv Hvperthermia Promotes The Therapeutic Effects On Breast Cancer When Combined With Heat Shock Protein Promoter-controlled HSV-TK Gene Therapy:Toward Interventional Molecular Imaging- Guided Gene Therapy

A lentiviral vector was first constructed using the heat shock protein (HSP) promoter (Phsp-) to precisely control the overexpression of a suicide gene, thymidine kinase (TK) (Phsp-TK). Serial in vitro experiments were performed to confirm the concept of using radiofrequency hyperthermia (RPH) to enhance PHSP-TK/lentiviral transduction and expression in a human breast cancer cell line. Serial in vivo experiments were then carried out to validate the feasibility of the new technique, interventional RFH-enhanced direct intratumoral PHsp-TK/ganciclovir gene therapy, in mouse models with the same breast cancers. The therapeutic effect of combination therapy was evaluated by magnetic resonance imaging (MRI) and confirmed by subsequent laboratory correlation.Results:In vitro experiments confirmed that, the combination treatment with Phsp-TK plus RFH resulted in significantly higher Phsp-TK gene transduction/expression, in comparison to other three controlled groups, as determined by real-time quantitative PCR. In addition, such combination therapy with Phsp-TK plus RFH also caused a lower cell proliferation rate and higher cell apoptosis index than those of control groups. In vivo validation experiments with MRI demonstrated that combination therapy resulted a significant reduction of relative tumor volume compared with those in control mice, and the in vivo results correlated well with corresponding histology and apoptosis analysis.Conclusion:The present study established "proof-of-principle" of a new technique, interventional RF hypothermia-enhanced local gene therapy for breast cancer, which may open new avenues for the effective management of breast cancers by simultaneous integration of interventional oncology, RF technology, and direct intratumoral gene therapy (instead of systemic gene therapy).