Hyperthermic therapy has been applied in many advanced malignancies, but tumor regression occurs only in thermo-sensitive cancers. To elucidate ways to overcome thermo-resistance and to improve the therapeutic efficiency of treating thermo-resistant cancers, we devised a novel application of cancer gene therapy in conjunction with hyperthermia. This strategy allows for selective cancer gene therapy under control of the heat-inducible HSP promoter. Heat-inducible activity of HSP promoter was examined in FM3A breast cancer cell line and MKN45 gastric cancer cell line using a luciferase assay reporter gene system. HSP promoter activity increased markedly following heat shock, and this increase depended on temperature and duration of treatment. Based on these results, we designed a suicide gene therapy using the Herpes simplex virus thymidine kinase gene ligated to the heat-inducible HSP promoter (HSP-tk). In in vitro cytotoxic assays HSP-tk transduced cells following heat treatment became 50, 000 times more sensitive than either non-transduced cells or HSP-tk transduced cells without heat treatment to ganciclovir (GCV). Immunohistochemical analysis revealed that Fas-mediated apoptosis was involved in the synergistic killing effect of combination therapy. Next, we examined the efficacy of HSP-tk gene therapy in vitro, cancer cell lines implants in subcutaneous or intraperitoneal models of balb/c nude mice were targeted using the HVJ-anionic-liposome method. Significant inhibition of tumor growth was observed in HSP-tk transduced tumors following hyperthermia as more than half of treated-mice showed complete tumor eradication. Prolonged survival was also observed in HSP-tk transducted mice with hyperthermia. In contrast, non-transduced mice treated with or without hyperthermia showed no prolongation of survival. Recently, another group reported an in vitro study that HSP promoter-mediated gene therapy is an effective treatment for prostate cancer studied. Taken together, these results demonstrate that the combined gene and hyperthermic therapy may be a feasible treatment that can target HSP-expressing carcinomas, even in advanced cases.

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Interactive effects of combined treatment with hyperthermia and chemotherapeutic agents were interpreted in the experimental aspects of medical science. Survey of literature and our own studies indicate that cytotoxicity of alkylating agents, cisplatin, bleomycin and mitomycin C (MMC) can be enhanced at elevated temperatures. However, the thermal enhancement of doxorubicin (Dox) is complicated or even doubtful against tumors, because Dox could potentially enhance production of heat-induced hsps that may cause the certain mechanism in the development of thermotolerance. Comparative studies indicated that the thermal enhancement of MMC cytotoxicity is marked and the development of thermotolerance was partially inhibited by MMC. An interesting observation is that the cytotoxicity of some drugs are enhanced by mild hyperthermia. In this regards, cisplatin (CDDP) potentiates cellular thermosensitivity at 42°C by enhancing heat-induced apoptosis. These findings are significant in use of chemotherapy together with mild hyperthermia which can avoid potential heat-induced normal tissue damage followed by the local or regional hyperthermia.

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Patients with an intrathoracic malignant tumor are often in a bad respiratory condition. Therefore, it is important to prove the safety of hyperthermia. We investigated body temperature, respiratory rate, blood pressure, pulse rate, percutaneous oxygen saturation and arterial blood gas analysis before, immediately after and 5 minutes after hyperthermia in 13 patients. Besides an increase in the pulse rate, which has already been reported, we observed an elevation of body temperature, increase of the respiratory rate and a depression of the partial pressure of oxygen in arterial blood. None was considered serious, but we need to remember these influences during hyperthermia.

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We investigated various materials used as electrodes for MRI RF interstitial heating. Coils or rods of iron, titanium, molybdenum, tungsten and copper were employed as samples for the internal electrode. For the external electrode, we tested copper foil and copper foil with a number of slits. The samples were each sandwiched between a pair of agar gel pieces, and we obtained T₁ weighted and phase images using an open type MRI system with 0.2T. The results showed that MR images were only slightly affected by the copper electrodes in comparison to the electrodes made from other materials. When the elasticity and density of the tested materials were taken into account, molybdenum was the most suitable for the inner electrode. The copper foil with slits affected the MR images less compared to the copper foil, and the former appears to be suitable for the external electrode for RF interstitial heating.

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