Winner of the Lund Science Award 1992 Thermosensitization induced by step-down heating: A review on heat-induced sensitization to hyperthermia alone or hyperthermia combined with radiation

Abstract

A few minute's exposure to a high temperature (sensitizing treatment, ST) may substantially increase the cytotoxic and the radiosensitizing effect of a subsequent heating at a lower temperature (test treatment, TT). This phenomenon, which is known as step-down heating (SDH) or thermosensitization, has been observed both in cultured cells in vitro and in tumours and normal tissues in vivo. The effect of SDH increases with a lowering of TT temperature, but it is rapidly lost at temperatures very close to 37 degrees C. SDH-induced thermosensitization decays within a few hours, when an interval is inserted between ST and TT. In vitro results suggest an exponential decay of the SDH effect with half times ranging from 1.5- to 3.1 h. The effect of SDH increases with increasing ST time or temperature. For single heating, the Arrhenius plot is biphasic with activation energies of 500-800 and 1200-1700 kJ/mol above and below a break point temperature in the region 42.5-43.0 degrees C, respectively. For SDH, the Arrhenius plot gradually becomes monophasic with increasing severity of ST and it approaches asymptotically to an activation energy of about 400 kJ/mol. The reduction of the activation energy depends on cell survival after the priming ST and not on the specific ST heating time or temperature. SDH strongly enhances hyperthermic radiosensitization with a 5-6-fold reduction of the radiation dose required to achieve tumour control. The thermosensitizing and the radiosensitizing effects of SDH have several features in common. Both effects become more prominent when the TT temperature is decreased and when the ST heating time or temperature increases. In addition, the decay kinetics for both effects are comparable. For heat alone, the effect of SDH in tumour and normal tissue seems to be quantitatively similar. However, the therapeutic ratio may be increased by combining SDH with radiation. Biologically, the critical subcellular targets involved in the SDH effect have not been revealed. However, the ability of SDH to inhibit the clearance of heat-induced aggregation of proteins in the nucleus is interesting. Blockage of the nuclear function by proteins is a central theory in the present molecular biological models for both cell kill by heat and heat radiosensitization. Clinically, SDH may be an advantage since even a short exposure to high temperature increases the effect of an otherwise inadequate heat treatment. The disadvantages are that SDH complicates thermal dose calculations, and may cause unacceptable damage to normal tissue.

Step-down heating of human melanoma xenografts: effects of the tumour microenvironment

“…The magnitude of the SDH effect in the xenograft lines was similar to that reported for the rodent tumour lines. The present study thus adds further support to the suggestion that the SDH effect is a general biological phenomenon applying also to clinical hyperthermia of human tumours (Lindegaard, 1992 Heat-induced vessel occlusion in tumours leads to secondary cell death (Kang et al, 1980;Rofstad & Brustad, 1986a), i.e. the tumour cells that were fully supplied by the collapsed vessels die because of rapid exhaustion of the oxygen and nutrient pools and/or accumulation of acidic waste products.…”

“…However, it has been suggested that the SDH effect might be explained in terms of inhibition of repair of sublethal heat damage (Henle, 1980) or enhanced conversion of sublethal heat damage into lethal damage (Jung, 1986;Henle, 1987;Lindegaard & Bentzen, 1993). SDH could be of direct clinical importance, sine even a short exposure to high temperature might increase the effect of an otherwise inadequate heat treatment (Lindegaard, 1992).…”

“…The cell inactivation following hyperthermic treatment is known to be modulated by heat itself (Henle, 1987;Lindegaard, 1992). A short exposure to a high temperature may increase the cytotoxic effect of a subsequent heat treatment at a lower temperature.…”

Effects of step-down and step-up heating on the development of thermotolerance in a C3H mammary carcinomain vivo

“…The present experiments are in agreement with these observations. SDH did not hamper the development of neither CIT nor AIT, thereby giving further support to the idea that thermosensitization and thermotolerance are independent phenomena (Jung 1982, Henle 1987, Lindegaard 1992.…”

“…Thermosensitization is observed with a high-tolow temperature sequence (step-down heating, SDH) and leads to an increased sensitivity to heating at the lower temperature (Joshi and Jung 1979, Henle 1980, Jung and Kolling 1980, Jung 1982, Lindegaard 1992. Thermotolerance can be expressed in at least two ways (Henle and Dethlefsen 1978, Bauer and Henle 1979, Field and Anderson 1982, Jung 1982, Dikomey et al 1984, Nielsen 1984, Henle 1987.…”