The tumor suppressor gene p53 encodes a transcription factor and is known to be the most frequently mutated gene (approximately 50%) in human cancer. The functional restoration of mutant p53 protein is considered to be one type of anticancer treatment ; and some chemical compounds, including CP-31398, PRIMA-1 (p53 reactivation and induction of massive apoptosis), and glycerol, have been shown to restore its function. We here investigated whether molecular chaperone inducers such as carbenoxolone (CBX), paeoniflorin (PF), and sodium salicylate (SA) could restore the functional defect of a temperature-sensitive mutant p53 protein (V143A). Functional restoration of p53 was detected by the induction of wild-type p53 activated fragment 1 (WAF1) and mouse double minute 2 (MDM2), both of which are gene products transactivated by an active p53. When H1299/tsp53 cells were cultured continuously at a nonpermissive temperature (37°C), no apparent expression of WAF1 and MDM2 was observed. Upon the temperature shift-down from 37°C to a permissive temperature (32°C), WAF1 and MDM2 gradually accumulated in the cells at 6 to 12 h later, probably owing to the gradual appearance of wild-type p53. When the cells were treated with molecular chaperone inducers at 37°C and then the temperature was shifted down, WAF1 and MDM2 appeared much earlier at 3 to 6 h, and also in much higher amounts than those in the control cells. Inhibition of molecular chaperone induction by quercetin or heat shock factor 1 (HSF1) siRNA diminished the facilitative effect of molecular chaperone inducers. Also, long-term overexpression (48 h) of molecular chaperones by CBX led to the accumulation of wild-type p53 even at 37°C. These results suggested that moderately overexpressed molecular chaperones could facilitate the correct folding and functional restoration of mutant p53 protein.

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Radiofrequency hyperthermia has been widely and successfully used for treatment of malignant tumors. Metastatic tumors are suppressed in some patients harboring malignant tumors during primary tumor treatment with hyperthermia. In the present study, regression of tumor size and visceral metastases were investigated in a mouse model involving treatment with local radiofrequency hyperthermia. 4T1/luc murine breast cancer cells were subcutaneously transplanted into the left thighs of female BALB/c mice. When the primary tumors reached a mean diameter of 5 mm, the tumors were treated with local 8 MHz radiofrequency hyperthermia two times a week for 3 weeks ; control animals were not treated with hyperthermia. In another group of mice, primary tumors were treated with doxorubicin injected into the tumor on day 7 after the tumor transplant, and were not treated with radiofrequency hyperthermia. The diameters of the primary tumors, the number of microscopic visceral metastasic foci, and luciferase activity in viscera were measured, and the results were compared between the groups of animals. Splenic lymphocytes were also examined using flow cytometry. Primary tumor growth was suppressed by both local radiofrequency hyperthermia and by intratumoral doxorubicin injection. However, lung metastases were inhibited only by local radiofrequency hyperthermia as shown by microscopic evaluation and luciferase activity assays. Liver metastases were not detected in any mice. The overall survival time was prolonged by local radiofrequency hyperthermia. The number of natural killer cells in the spleen was significantly increased after treatment with local radiofrequency hyperthermia, and this increase in natural killer cells in the spleen might account for the inhibition of lung metastases. In conclusion, primary tumor growth and the frequency of lung metastases were reduced by local radiofrequency hyperthermia treatments in the 4T1/luc mouse model.

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A robust non-invasive technique for reconstructing the thermal properties of living tissues-thermal conductivity, thermal capacity and thermal diffusivity - and thermal quantities such as thermal source/sink and perfusion for diagnosis, and monitoring and planning thermal treatments such as a high-intensity focused ultrasound (HIFU) and interstitial radio frequency (RF) or microwave electromagnetic coagulation therapy are reported. Internal tissue temperature distributions can be measured using ultrasonic imaging or magnetic resonance imaging. When performing a reconstruction after stopping heating and perfusion, only the thermal properties are reconstructed. However, because the region of interest may include thermal source and the perfusion cannot always be stopped, by increasing the independent temperature field data, the thermal source and perfusion can also be reconstructed. The feasibilities of the reconstructions of thermal source and perfusion are respectively verified by simulations. Although the increase in the number of equations leads to unstable results for the reconstruction of perfusion, our developed regulation is effective for stabilizing the reconstruction.

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