Hyperthermia Cancer Therapy Research Articles

Induction of Thermotolerance and Evidence for a Well-Defined, Thermotropic Cooperative Process

Heat-induced thermal resistance is not only an interesting biological phenomenon, but may also present an important consideration in the application of hyperthermia in cancer therapy. Characterization of the temperature dependence and kinetics of the induction of thermotolerance serves two purposes. First, such data are essential to the rational design of clinical heat treatment protocols, and second, knowledge of the kinetics and temperature dependence may yield some insight into the mechanism of thermotolerance and thermal inactivation. Split-dose experiments were performed using plateau-phase Chinese hamster HA-1 cells. The effects of varying the temperature (41-470C) and the duration of the first heat treatment on the subsequent expression of thermotolerance were studied. Our results indicate that cells initially treated at 41 and 420C are essentially at their most resistant state at the end of the first treatment, while an initial exposure to 430C or higher requires approximately 8 hr of incubation at 370C before maximal thermotolerance is expressed. Based on our three-component model of thermotolerance (trigger-development-decay), we found that neither the rate of development nor the rate of decay was significantly affected by the duration of the first treatment. By plotting the survival at maximal thermotolerance as a function of the duration of the initial heat treatment (at temperatures of 40-470C), we were able to display the kinetics of the trigger. From these data we constructed an Arrhenius plot which yielded two linear, parallel segments with an unusually sharp discontinuity near 43?C. Over both temperature ranges, 43-47 and 40-42.50C, the activation energy is approximately 120 kcal/mole, consistent with the involvement of protein structure alterations in the heat-actuated event. Furthermore, the discontinuity in the Arrhenius plot implies the existence of a sharp thermotropic cooperative process occurring at approximately 430C.

Preliminary experience with irradiation and local microwave hyperthermia in cancer therapy

Preliminary experience with irradiation and local microwave hyperthermia in cancer therapy

Localized hyperthermia for cancer therapy what treatment data should be collected?

Localized hyperthermia for cancer therapy what treatment data should be collected?

Heating techniques in hyperthermia. I. Introduction and assessment of techniques.

During the last decade there has been great interest in the use of hyperthermia in cancer therapy. The reasons why elevated temperatures, either alone or together with radiotherapy or chemotherapy, may prove useful have been the subjects of several recent reviews (Connor et al., 1977; Field and Bleehen, 1979).* Clinical applications of hyperthermia fall into two broad categories—whole-body and localized hyperthermia. During whole-body hyperthermia, which has been used on patients with advanced and widespread malignancies, core temperature is maintained at 41.8–42°C for a few hours. This appears to be the range of maximum tolerated temperatures; the organs which limit such treatment are the liver, which may be relatively sensitive to thermal damage, and the heart. Methods of inducing whole-body hyperthermia include the use of wax baths (Pettigrew et al., 1974), hot air cabinets (Pomp, 1978), water blankets (Barlogie et al., 1979) and space suits (Bull et al., 1979). Common features of these methods are the reduction of heat losses from the patient and the introduction of thermal energy into the body to enable the desired level of hyperthermia to be reached rapidly. The heating techniques and associated monitoring of temperature are relatively simple and no further comment on them will be made here. Local hyperthermia offers a wider range of therapeutic possibilities, especially if the temperature in a tumour can be maintained above that of surrounding normal tissue.

Hyperthermic modification of cyclophosphamide metabolism in rat hepatic microsomes and liver slices

The ability of rat liver microsomes and liver slices to metabolize the antineoplastic compound cyclophosphamide was studied at 37° and at elevated temperatures comparable to those used for human systemic hyperthermic antineoplastic therapy. Temperatures above 40.5° and 41.8° inhibited cyclophospamide metabolism by microsomes and liver slices respectively. Therefore, cyclophosphamide may not be a suitable drug for combination with systemic hyperthermia in cancer therapy.

Heat-induced Thermal Resistance and Its Relationship to Lysosomal Response

Two separate effects of hyperthermia on mouse splenic lysosomes have been reported, dependent on the severity of the treatment. Heating to temperatures below 42.5 degrees C causes a transient increase in lysosomal acid phosphatase activity which can be correlated with the ability of moderate hyperthermia to potentiate X-ray damage. Heating to temperatures above 42.5 degrees C results in an immediate increase in lysosomal membrane permeability which may be involved in tissue necrosis. By giving a priming heat treatment at 41.8 degrees C, induced thermal resistance was demonstrated for the lysosomal membrane effect, but not for the enzyme activation. The degree of induced thermal resistance observed is similar to that reported for the cell-killing effect of heat on tissues in vivo and cells in vitro and occurs over a similar time course. The relevance of these results to the understanding of fractionated hyperthermia in cancer therapy is discussed.

Cellular Responses to Combinations of Hyperthermia and Radiation

The two principal rationales for applying hyperthermia in cancer therapy are that: (a) the S phase, which is relatively radioresistant, is the most sensitive phase to hyperthermia, and can be selectively radiosensitized by combining hyperthermia with x-irradiation; the cycling tumor cells in S phase which would normally survive an x-ray dose could thus be killed by subjecting these cells to hyperthermia; and (b) the relatively radioresistant hypoxic cells in the tumor may be selectively destroyed by combinations of hyperthermia and x-irradiation. Both of these rationales have been mentioned as reasons for using high LET irradiation in cancer therapy; therefore where such irradiation may be of use, hyperthermia may also be advantageous.

Heat in Tumor Therapy

To the Editor.— Le Veen et al (235:2198, 1976) describe their experience in treating 21 cancer patients with hyperthermia induced by radiofrequency (RF) diathermy. Their clinical results, though anecdotal, are consistent with the conclusion that if the temperature of tumors are elevated above the thermal death point for tissue, necrosis will result. This is not a surprising conclusion, and is in fact the basis of electrocautery. These results should not be confused with hyperthermic cancer therapy in the range of 42 to 45 C, in which destruction of tumor cells can be achieved without necrosis.1 The authors imply that their technique of heating is unique. This is hardly the case. An RF heating system for localized hyperthermia has been described by Gerner et al2and is actively used by that group. Furthermore, an RF unit specifically for tumor hyperthermia and operating at precisely the frequency described by Le

Combinations of hyperthermia (40 degrees, 45 degrees C) with radiation.

Incubation of Chinese hamster cells at an elevated but sublethal temperature between fractions of radiation and/or pulses of hyperthermia at 45 degrees C strongly modified the effectiveness of cell killing. Increasing the incubation temperature from 37 to 40 degrees C between fractions of hyperthermia at 45 degrees C followed by radiation substantially enhanced cell killing; while the opposite sequence (radiation leads to incubation at 40 degrees C leads to hyperthermia at 45 degrees C) resulted in less effective cell killing than would have been expected from the independent interaction of hyperthermia and radiation alone. This suggests the use of short pulses of localized hyperthermia in the presence of physiologically tolerable fever followed by irradiation as one approach to the utilization of hyperthermia in cancer therapy.