Hyperthermia (HT) combined with chemotherapy, radiotherapy or both has been considered a promising approach in cancer therapy. However, one of the problems with the use of HT is the acquisition of thermotolerance (TT), which makes HT less effective. The endoplasmic reticulum (ER) is the central intracellular organelle responsible for the quality control of newly synthesized proteins. ER stress―defined as the accumulation of unfolded proteins in the ER―induces a cytoprotective program, the ER stress response, also known as the unfolded protein response (UPR). ER stress can be triggered by various pathophysiological conditions, such as heat shock, glucose starvation, hypoxia, and calcium deprivation. This response is mediated through three distinct sensor molecules, IRE1 (inositol requiring enzyme-1), PERK (protein kinase R-like ER kinase), and ATF6 (activating transcription factor 6), which locate at the ER membrane. Under nonstress conditions, BiP (HSPA5: heat shock protein family A (Hsp70) member 5) interacts with these sensor molecules. In contrast, under ER stress conditions, BiP dissociates from the protein conjugate, leading to the activation of three sensor molecules. Interestingly, IRE1, PERK and/or ATF6 signaling pathways are found to be activated in the cells treated with heat stress.

In this review, the physiological roles of ER stress response in HT and TT are summarized.

Cancer clinical research using heat-generating nanoparticles named magnetite cationic liposomes (MCL) and alternating magnetic field (AMF) irradiator has been conducted. Heat generation from intratumorally injected MCL particles was triggered by AMF irradiation to kill cancer cells nearby located. Tumor temperature was monitored as index to control treatment condition but efficacy was variable from complete regression to ineffective. In order to improve efficacy, we have proposed novel index of heat dose in vivo (J/cm3 tumor volume). Purpose of this study was to reveal actual heat dose in vivo and discuss its utility as index.

In order to enable to estimate heat dose, heat generation activity of MCL particles (J/g-MCL・min) was measured under various AMF irradiation conditions by changing output power (kW) and distance from irradiation surface (mm). Treatment condition for complete regression of animal tumors with 7 mm diameter was reproduced and heat dose in vivo (J/cm3) was calculated by multiplying heat generation activity (J/g-MCL・min) with MCL dosage (g-MCL/cm3) and irradiation time (min). Heat dose for tumor regression was revealed around 700-850 J/cm3 in every thrice AMF irradiations of a course. Since temperature-based treatments of large tumors were reported to fall into insufficiency, revealed heat dose was applied to design treatment condition of large tumor with 13-16 mm diameter, and complete regression was achieved by a course treatment. MCL dosage of temperature-based condition was found far lower than that of heat dose. Low MCL dosages (g-MCL/cm3) would cause shortage of heat dose (J/cm3) and insufficient anticancer activity, although tumor temperature could be raised by heat transfer to monitoring sites. These results showed utility of heat dose in vivo as index to ensure clinical efficacy and concomitantly to make useless invasive probe for temperature monitoring. Procedure to design treatment condition and required performance of AMF irradiator were described.

RF Capacitive-type heating device (8 MHz) manufactured by Yamamoto Vinita Co., Ltd., improved the generator from EX edition with self-excited oscillator using tube to GR edition with solid-state amplifier using crystal oscillation, which led to downsizing. To prove heating characteristics of the new device, we compared the heating performance of both devices on basic heating characteristics and assumed clinical use using agar phantoms. 1) Waveforms of RF generated by both devices were similar, and those were not distorted. 2) In the experiment using a phantom for measuring the heating electricity, both devices were able to uniformly heat the phantom, and those heating efficiencies were 63 and 64%, respectively. 3) A phantom was sandwiched between a pair of electrodes, the diameter of lower electrode was fixed at 30 cm, and that of upper electrode was changed from 30 to 7 cm. The range of the heating area became shallower as the electrode became smaller. Those phenomena were same on both devices. 4) In case of a protrusion on upper side of the phantom, the temperature rise of the protrusion was higher than its surroundings. Those tendencies were same on both devices. 5) When there was an air cavity in the phantom, the temperature rises in the phantom near the air cavity facing the electrode was small, and that not facing the electrode was large. Those phenomena were the same on both devices. 6) When there was a bone in the phantom, the temperature rises in the phantom near the bone facing the electrode was small, and that not facing it was large. The temperature of the bone itself rose a little. Those phenomena were same on both devices. 7) Regardless of electrodes set in parallel or not parallel, the temperature distributions of the depth direction were same. But the temperature rises in one side of the phantom at the closer distance between two electrodes rose larger than the opposite side. Those phenomena were same on both devices. From the above, the heating device GR edition using the solid-state amplifier is upward compatible with respect to the heating device EX edition using the oscillating tube.