Orthotopic Esophageal Cancers: Intraesophageal Hyperthermia-enhanced Direct Chemotherapy in Rats

Shi, Yaoping; Zhang, Feng; Bai, Zhang; Wang, Jianfeng; Qiu, Lina; Li, Yonggang; Meng, Yanfeng; Valji, Karim; Yang, Xiaoming

doi:10.1148/radiol.2016152281

Cited by 11 publications

(9 citation statements)

References 26 publications

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“…Previous studies from our group and other groups have confirmed that mild hyperthermia (42-44°C) can enhance the therapeutic effect of chemotherapy of HCCs [ 24 ]. However, both primary and metastatic hepatic malignancies can develop resistance to chemotherapy, primarily caused by tumor-initiating cells [ 25 ].…”

Section: Discussionmentioning

confidence: 68%

Orthotopic hepatic cancer: radiofrequency hyperthermia-enhanced intratumoral herpes simplex virus-thymidine kinase gene therapy

et al. 2017

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PurposeTo validate the feasibility of using interventional radiofrequency hyperthermia(RFH) to enhance herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) gene therapy of rat orthotopic hepatic cancer.Material and MethodsRat hepatocellular carcinoma cells (MCA-RH-7777) were transduced with lentivirus/luciferase gene for optical imaging. In-vitro experiments with the luciferase cells and in-vivo experiments on rats with orthotopic hepatic tumors were divided into four treatment groups: (i) HSV-TK/GCV-mediated gene therapy combined with RFH; (ii) gene therapy alone; (iii) RFH alone; and (iv) phosphate buffered saline (PBS). Cell viability was evaluated by MTS assay and confocal microscopy, and HSV-TK gene expression in cells and tumors was quantified by western blotting. Bioluminescent optical imaging and ultrasound imaging were used to monitor and compare the photon signal and tumor size changes among different treatment groups overtime, respectively. The imaging findings were correlated with histology.ResultsFor in-vitro experiments, the combination therapy group (gene therapy + RFH) demonstrated the lowest cell proliferation by MTS assay, compared to the gene therapy alone, RFH alone, and PBS (26.1±3.2% vs 50.4±4.6% vs 82.9±6.3% vs 100%, p<0.01). The combination therapy group also showed fewer survived cells by the confocal microscopy and the lowest bioluminescent signal by the optical imaging. For in-vivo experiments, the combination therapy group demonstrated a significantly decreased signal intensity on the bioluminescent optical imaging (0.57±0.09, 1.06±0.10 vs 3.43±0.27 vs 3.85±0.12, p<0.05) and smallest tumor volume by ultrasound imaging (0.28±0.11 vs 1.28±0.23vs 4.64±0.35 vs 6.37±0.36, p<0.05), compared to the other three groups. Additionally, these imaging findings correlated well with the histological confirmation.ConclusionIt is feasible to use RFH to enhance HSV-TK/GCV gene therapy of hepatic tumors in in-vitro and in-vivo settings, as assessed by molecular imaging. This technical development may provide a novel opportunity for effective treatment of liver malignancies by employing simultaneous integration of radiofrequency technology, interventional oncology, and direct intratumoral gene therapy.

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Section: Discussionmentioning

confidence: 68%

Orthotopic hepatic cancer: radiofrequency hyperthermia-enhanced intratumoral herpes simplex virus-thymidine kinase gene therapy

et al. 2017

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“…Previous studies have shown that RFH may enhance the direct intra-tumoral chemotherapy effects on human cancers (8,9). Though HSP70 has been shown to be a potent activator of innate immunity, the immunological consequences mediated by their expression in RFH-treated tumors have not been explored.…”

Section: Discussionmentioning

confidence: 99%

Image-Guided Radiofrequency Hyperthermia (RFH)-Enhanced Direct Chemotherapy of Hepatic Tumors: The Underlying Biomolecular Mechanisms

et al. 2021

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PurposeTo evaluate the treatment effect of radiofrequency-induced hyperthermia (RFH) combined with intra-tumoral chemotherapy for rabbit VX2 liver tumors and explore the underlying mechanism that drives local hyperthermia-enhanced chemotherapy.Materials and MethodsVX2 cell lines and rabbits with liver VX2 tumors were randomly allocated to four treatment groups including: (1) combination therapy of Doxorubicin (DOX) plus hyperthermia/RFH (n=6); (2) DOX only; (3) hyperthermia/RFH only (n=6); and (4) phosphate-buffered saline-treated control (n=6). Cell viability and doxorubicin uptake by VX2 tumor cells were assayed using flow cytometry and fluorescence microscopy 24 h after treatments. Western blot was used to evaluate the expression level of heat shock protein 70 (HSP70) in tumor cells and tissues. For the harvested VX2 tumors, fluorescence microscopy was used to evaluate the distribution and penetration of doxorubicin in tumor tissues and HSP70 expression was analyzed by Western blot and immunohistochemistry.ResultsRFH enhanced the chemotherapeutic effect of doxorubicin in VX2 cells and rabbit liver VX2 tumors resulting in higher apoptosis and lower cell viability. Flowcytometry of VX2 cells showed more apoptotic cells in combination therapy of hyperthermia and DOX, compared with other three groups in-vitro experiments (45.80 ± 1.27% vs 20.66 ± 0.71%, vs 15.16 ± 0.81% and 0.62 ± 0.06%, respectively, p<0.01). The quantitative analysis by Western blot and immunohistochemistry showed increased expression of HSP70 in both VX2 tumor cells (1.28 ± 0.13 vs 0.64 ± 0.13 vs 0.83 ± 0.10 vs 0.15 ± 0.03, respectively, p<0.05) and tumors (1.47 ± 0.13 vs 0.51 ± 0.13 vs 0.74 ± 0.11 vs 0.16 ± 0.04, respectively, p <0.01). Fluorescence microscopy showed increased uptake of DOX in tumor cells in the combination therapy group.ConclusionsRFH/hyperthermia enhanced the chemotherapeutic effect of DOX in VX2 tumors by promoting the uptake of DOX and the expression HSP70 in tumors.

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“…Recent studies from our group and others have successfully confirmed that image-guided interventional radiofrequency hyperthermia (RFH, at a sub-lethal temperature <60°C) can greatly enhance chemo- and gene therapies of malignancies in various organs ( 19 – 21 ). The recognized mechanisms of RFH-enhanced therapies include tissue fracture via heating, increased permeability of cytoplasmic membranes, disruption of cellular metabolism, activation of membrane associated pumps, and activation of the heat shock protein pathway ( 22 – 24 ).…”

Section: Introductionmentioning

confidence: 93%

Interventional Optical Imaging-Monitored Synergistic Effect of Radio-Frequency Hyperthermia and Oncolytic Immunotherapy

et al. 2022

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PurposeTo develop a new interventional oncology technique using indocyanine green (ICG)-based interventional optical imaging (OI) to monitor the synergistic effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immunotherapy.Materials and MethodsThis study included (1) optimization of ICG dose and detection time-window for intracellular uptake by VX2 tumor cells; (2) in-vitro confirmation of capability of using ICG-based OI to assess efficacy of RFH-enhanced oncolytic therapy (LTX-401) for VX2 cells; and (3) in-vivo validation of the interventional OI-monitored, intratumoral RFH-enhanced oncolytic immunotherapy using rabbit models with orthotopic liver VX2 tumors. Both in-vitro and in-vivo experiments were divided into four study groups (n=6/group) with different treatments: (1) combination therapy of RFH+LTX-401; (2) RFH alone at 42°C for 30 min; (3) oncolytic therapy with LTX-401; and (4) control with saline. For in-vivo validation, orthotopic hepatic VX2 tumors were treated using a new multi-functional perfusion-thermal radiofrequency ablation electrode, which enabled simultaneous delivery of both LTX-401 and RFH within the tumor and at the tumor margins.ResultsIn in-vitro experiments, taking up of ICG by VX2 cells was linearly increased from 0 μg/mL to 100 μg/mL, while ICG-signal intensity (SI) reached the peak at 24 hours. MTS assay and apoptosis analysis demonstrated the lowest cell viability and highest apoptosis in combination therapy, compared to three monotherapies (P<0.005). In in-vivo experiments, ultrasound imaging detected the smallest relative tumor volume for the combination therapy, compared to other monotherapies (P<0.005). In both in-vitro and in-vivo experiments, ICG-based interventional optical imaging detected a significantly decreased SI in combination therapy (P<0.005), which was confirmed by the “gold standard” optical/X-ray imaging (P<0.05). Pathologic/laboratory examinations further confirmed the significantly decreased cell proliferation with Ki-67 staining, significantly increased apoptotic index with TUNEL assay, and significantly increased quantities of CD8 and CD80 positive cells with immunostaining in the combination therapy group, compared to other three control groups (P<0.005).ConclusionsWe present a new interventional oncology technique, interventional optical imaging-monitored RFH-enhanced oncolytic immunotherapy, which may open new avenues to effectively manage those patients with larger, irregular and unresectable malignancies, not only in liver but also the possibility in other organs.

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Orthotopic Esophageal Cancers: Intraesophageal Hyperthermia-enhanced Direct Chemotherapy in Rats

Cited by 11 publications

References 26 publications

Orthotopic hepatic cancer: radiofrequency hyperthermia-enhanced intratumoral herpes simplex virus-thymidine kinase gene therapy

Orthotopic hepatic cancer: radiofrequency hyperthermia-enhanced intratumoral herpes simplex virus-thymidine kinase gene therapy

Image-Guided Radiofrequency Hyperthermia (RFH)-Enhanced Direct Chemotherapy of Hepatic Tumors: The Underlying Biomolecular Mechanisms

Interventional Optical Imaging-Monitored Synergistic Effect of Radio-Frequency Hyperthermia and Oncolytic Immunotherapy

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