Using chemotherapy alone, it is difficult to cure patients with solid tumors. However, chemotherapy combined with heat treatment enhances cytotoxicity by improving drug delivery to tumor tissues, leading to improvements in the cure rate.
Nuclear factor-kappa B (NF-κB) has been reported to be activated by chemotherapy in some cancer cell lines, and NF-κB activation is one mechanism through which tumors can become resistant to chemotherapy. Heat treatment-induced heat shock protein 70 (Hsp70) was reported to inhibit I kappa B (Iκ-B) kinase (IKK), resulting in the inhibition of NF-κB activation. In view of this observation, it appeared to be possible that activation of NF-κB in a pancreatic cell line might be inhibited by heat treatment, leading to an enhancement of gemcitabine-induced cytotoxicity. However, the timing of the heat treatment is also very important in producing chemosensitization when combined with chemotherapy.
In this review, the timing of a heat treatment in relation to a gemcitabine treatments is discussed, along with the mechanisms leading to sensitization in combination therapy.

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Hyperthermia (HT) using a 8-MHz radiofrequency-capacitive heating device at University of Occupational and Environmental Health (UOEH) was initiated in 1988, and over 1000 patients have been treated with HT. The heat had been performed by radiation oncologist for long period. In recent years, it has been supported by medical engineer and nurse as instructed in radiation oncologist. Basically, HT has been performed concurrent with radiotherapy or chemoradiotherapy, and the combined therapy of systemic chemotherapy with regional HT has been increasing since 2004. Recently, advances in physics for radiotherapy cause a significant improvement of tumor control rates. However, a further improvement of the local tumor control rate is still demanded for a lot of locally advanced cancer or loco-regional recurrent cancer. The regional HT may remain important role for those advanced tumors. In the patients with locally advanced lung or esophageal cancers, the combined therapy of chemoradiotherapy and regional HT has been used actively at UOEH. In addition, we have tried the adding of regional HT in the patients with the limited treatment choices, such as re-irradiation for the patients with in-field recurrence, and re-administration of chemotherapy for multidrug-resistant cases. Here, we review current status of HT, especially for heating methods of deep regional HT, at UOEH, and discuss future direction for deep regional HT to improve clinical outcome of HT inclusive therapy.

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This aim of the work described here was to determine the effect of an ataxia-telangiectasia mutated protein (ATM) kinase inhibitor on thermo- and/or radio-sensitivity in normal human fibroblasts cells and in osteosarcoma cells in the plateau or confluent phase of cell growth. Cell survival and chromosome aberrations were observed when cells were exposed to a heat shock at 45°C and/or γ-rays in the presence or absence of an ATM kinase inhibitor. Cell survival was measured with colony formation assays. Chromosome aberrations were observed using chemically induced premature chromosome condensation and fluorescence in situ hybridization. Cellular radiosensitivity was enhanced in both cell lines by a heat shock treatment at 45°C. Adding an ATM kinase inhibitor amplified this effect. Furthermore, thermosensitivity in both cell lines at 45°C was enhanced by treatment with an ATM kinase inhibitor. Heat shock treatments at 45°C enhanced the frequency of chromosome aberrations induced by γ-irradiation in both cell lines ; in the presence of an ATM kinase inhibitor, the frequency of chromosome aberrations was enhanced. Thus, ATM kinase inhibitors increased the number of heat-induced aberrations. These results were observed in both, normal human fibroblasts cells and osteosarcoma cells. ATM kinase inhibitors can contribute to heat-induced cell killing and to heat-induced cellular chromosome aberration frequencies in the plateau or confluent phase of cell growth.

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