Is it possible to produce the specific death of tumor tissue using hyperthermia? An answer requires an understanding of the temperatures used. Hyperthermia at 43°C or above causes acute vascular disturbance and protein degeneration in all tissues, leading to the necrosis of tumors. Radiofrequency ablation (RFA) is a tumor-specific physiological targeting method for small tumors, and hence, biology may not greatly contribute to the progress of such a high-temperature therapy. In selective targeting of tumors with mild-temperature hyperthermia (MTH), two separate issues require consideration : the effect on the tumor cells themselves and the effect on the tumor environment. In targeting tumor cells, optimal MTH efficacy is dependent on the inhibition of thermotolerance. The availability of a drug that selectively inhibits the expression of hsp could render MTH an effective form of anti-tumor therapy. At present, however, because MTH itself has only a weak effect on tumors, some method of concomitant therapy is necessary. Studies involving concomitant treatment of MTH with low-dose-rate (LDR) irradiation or pulsed-dose-rate (PDR) irradiation have shown that the combination of MTH with irradiation allows the inhibition of tumor recovery from sublethal damage inflicted by a rise in temperature of just 1 or 2°C. Because MTH induces not only an increase of the expression of tumor-specific antigens, but also an increase in the uptake of antibodies over an extended period by altering hemodynamics, recommended clinical use is in combination with radioactive monoclonal antibody therapy. MTH has also gained attention in the field of gene therapy. The activation of hsp by heat produces a dynamic response, and attempts are now underway to promote the efficient expression of a cytotoxic cytokine gene within tumors using an hsp 70 promoter. With regard to targeting of the tumor environment, the effect of MTH on tumor blood vessels is important. MTH has been shown to improve intratumoral hypoxia, while more recent drug-delivery research has investigated the use of MTH in the selective uptake of antitumor drugs. This review will outline these new research results and address the question of how hyperthermia can be used effectively in tumor therapy.

View full abstract

Single exposure of cells to hyperthermic treatment, makes them thermotolerant to subsequent heat treatment. Tumor cells that express normal or elevated levels of HSPs show thermotolerence. KNK437, a chemically synthesized benzylidene lactam compound, has been specifically found to inhibit the synthesis of heat shock proteins and thus leading to significant reduction in the thermotolerance of cells. However, mechanisms by which KNK437 inhibits thermotolerence are still not clearly understood. In this study an attempt has been made to elucidate the mechanisms of inhibition of HSPs by KNK437 in 2 cell lines of human oral squamous cell carcinma with varying sensitivities (HSC4 ; heat-resistant and KB ; heat-sensitive) with an aim to identify which of the HSPs are targeted by KNK437. Single administration of 100μM KNK437-treatment always resulted in a higher than 85% cell survival compared to the untreated groups, indicating the KNK437 had a minimum cytotoxic effect in both cell lines. Combination of hyperthermia with KNK437 after heat shock, specifically inhibited the induction of HSPs, where the expression of HSP27, HSP40, HSP70 and HSP90 reduced in a time dependent manner. Interestingly, the hyperthermic treatment combined with KNK437 produced supra-reductive effect on the expression of HSP27 and HSP90 in HSC4, HSP27, HSP40 and HSP90 in KB cells, when compared to heat treatment alone. Our results indicate that inhibition of HSPs by KNK437 plays an important role in inhibiting the thermotolerence of the cells and may be a valuable to improve the efficacy of oral cancer during hyperthermic therapy.

View full abstract

We report a patient with paralysis and severe lumbago due to a vertebral metastasis from rectal cancer, who was successfully treated with thermo-radiotherapy plus chemotherapy and hyperbolic oxygen therapy. The patient underwent 40Gy of radiotherapy, 12 sessions of hyperthermia and 16 sessions of hyperbolic oxygen therapy combined with weekly chemotherapy. His symptoms were gradually improved after start of the treatment, lumbago was relieved at the end of radiotherapy, and he became ambulatory. The patient was also treated for other distant metastases with radiotherapy, hyperthermia and chemotherapy continuously with keeping good quality of life during eight months after the completion of the treatments for vertebral metastasis. Combination of radiotherapy, hyperthermia, chemotherapy and hyperbaric oxygen therapy may be effective for complete paralysis due to vertebral metastasis in inoperative cases.

View full abstract