Abstract
ObjectiveGene therapy is a frontier in modern medicine. In the present study, we explored a new technique for the effective treatment of multidrug-resistant (MDR) breast cancer by combining fully the advantages of multidisciplinary fields, including image-guided minimally invasive interventional oncology, radiofrequency technology, and direct intratumoral gene therapy.ResultsCombination treatment with PHSP-TK plus RFH resulted in significantly higher TK gene transfection/expression, as well as a lower cell proliferation rate and a higher cell apoptosis index, than those of control groups. In vivo validation experiments with MRI confirmed that combination therapy resulted in a significant reduction of relative tumor volume compared with those of control animals, which was supported by the results of histologic and apoptosis analyses.Materials and methodsThe heat shock protein promoter (PHSP) was used to precisely control the overexpression of thymidine kinase (TK) (PHSP-TK). Serial in vitro experiments were performed to confirm whether radiofrequency hyperthermia (RFH) could enhance PHSP-TK transfection and expression in a MDR breast cancer cell line (MCF7/Adr). Serial in vivo experiments were then carried out to validate the feasibility of the new technique, termed interventional RFH-enhanced direct intratumoral PHSP-TK gene therapy. The therapeutic effect of combination therapy was evaluated by MRI and confirmed by subsequent laboratory correlation.ConclusionsThis study has established “proof-of-principle” of a new technique, interventional RFH-enhanced local gene therapy for MDR breast cancer, which may open new avenues for the effective management of MDR breast cancers via the simultaneous integration of interventional oncology, RF technology, and direct intratumoral gene therapy.
Highlights
Breast cancer is the most common malignancy in women worldwide, accounting for 29% of new cancer cases among women in 2015, with an estimated annual mortality rate of 15% in the United States [1]
The PHSP-thymidine kinase (TK) plasmid was transfected into MCF7/ Adr cells, and detection of GFP fluorescence indicated the successful expression of the PHSP-TK gene (Figure 1B)
This was confirmed by performing cell proliferation assays, the results of which showed that combination treatment with PHSP-TK plus radiofrequency hyperthermia (RFH) significantly inhibited tumor cell proliferation, resulting in a lower cell viability rate (3.8% ± 0.2%) than that of the other treatment groups (100% ± 3.22% vs. 91.4% ± 3.7% vs. 49.8% ± 2.0% vs. 92.6% ± 6.4% vs. 73.3% ± 5.5%, Control, Mock, PHSP-TK, RFH, and RFH + Mock groups, p < 0.0001) (Figure 3B)
Summary
Breast cancer is the most common malignancy in women worldwide, accounting for 29% of new cancer cases among women in 2015, with an estimated annual mortality rate of 15% in the United States [1]. Adjuvant chemotherapy can reduce the risk of metastatic recurrence after surgical removal of breast cancer. Currently-available chemo-drugs are effective only in certain subgroups of patients with breast cancer because they target specific proteins within tumors (e.g., trastuzumab targets breast cancers with HER2 expression). Multidrug resistant (MDR) breast cancer leads to recurrence at distant metastatic sites in a proportion of www.impactjournals.com/oncotarget breast cancer patients after adjuvant chemotherapeutic treatment. Drug resistance to chemotherapy can be divided into two types: intrinsic and acquired. Intrinsic resistance comprises cancers that possess chemodrug resistance related factors before the initiation of chemotherapy. Acquired resistance denotes cancers that acquire chemotherapy resistance during chemotherapy after being initially chemodrug sensitive, This may be caused by mutations or the activation of compensatory signaling pathways [2]
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