Laurie Rice

Studies on fractionated hyperthermia in experimental animal systems II. Response of murine tumors to two or more doses

The effect of multiple hyperthermia and the kinetics of thermal resistance were studied in experimental murine tumors. A spontaneous C3Hf mouse mammary carcinoma, MCa had a chemically-induced fibrosarcoma, FAa-1, were used. Assay methods included determination of the TCD50, i.e., the treatment time to yield a tumor control in half the treated animals and TG (tumor growth) time analysis, i.e., the time required for a tumor to reach a given size after first treatment. After equal dose fractions the TCD50 of MCa increased with increasing overall treatment time. This increase was most predominant when treatments were given with a time interval of one day. Isoeffect curves for the MCa were comparable to those for normal tissue damage (foot reaction), which was reported in the first part of this series of communications. The kinetics of thermal resistance in the MCa was compared with that in FSa-I since the fractionated hyperthermia for the FSa-I was reported to have resulted in an appreciable therapeutic gain. The magnitude of thermal resistance was far greater in the MCa than in the FSa-I, although the kinetics of thermal resistance was similar in both tumors; i.e., (a) the resistance reached a maximum in 24 hours after treatment and then decayed slowly, and (b) the development of thermal resistance increased with increasing initial dose. The thermal resistance in these tumors appeared to be greater than that in animal feet.

The Kinetics of Thermotolerance in the Mouse Foot

The kinetics of thermotolerance, which is defined as the transient resistance to hyperthermia following an initial heat treatment, was studied in a normal tissue system of C3Hf/Sed mice. Hyperthermia was given by immersing animal feet in a water bath at 45.5 ± 0.1°C. A priming dose was followed by various second doses and the treatment time necessary to induce loss of one toe or a greater reaction in half the treated animals, i.e.,

Studies on fractionated hyperthermia in experimental animal systems I. The foot reaction after equal doses: Heat resistance and repopulation

{\rm RD}_{50}

Thermal resistance in a spontaneous murine tumour

, was determined. The kinetics of thermotolerance was dependent upon the size of priming dose and the duration of the intertreatment interval. Following the first treatment, thermotolerance developed fully within 24 hr. A smaller priming dose was associated with a more rapid development of thermotolerance. Complete decay of the tolerance was not evident in the first 5 days after the priming dose. The magnitude of thermotolerance increased with the size of first dose. The thermotolerance ratio was approximately 4.5 times greater after a primin...

The radiosensitivity of a murine fibrosarcoma as measured by three cell survival assays.

Abstract The response of the mouse foot to fractionated hyperthermia was studied in vivo . Hyperthermia was given by immersing the mouse foot into a constant temperature water bath kept at 43.5 ± 0.1°C. Foot reaction was scored after treatment according to a numerical score system; at 43.5°C the time to induce loss of one toe or a greater reaction in half the treated animals (RD 50 ) was assayed. The equal dose fractions were used throughout the present experiments. The RD 50 for various time intervals (Ti) between two doses demonstrated rapid development of heat resistance which reached a maximum in 48 hours after first treatment. The resistance subsided thereafter and the complete decay of resistance required almost 2 weeks. If 2 doses were given with a Ti of more than 17 days, further increase of the RD 50 was observed, which might be attributed to repopulation of surviving cells. Isoeffect curves for treatment schedules with various Ti were obtained. These studies indicated that heat resistance develops repeatedly after each treatment and is the most important factor in fractionated hyperthermia. The kinetics of the resistance appeared to depend on the Ti and number of fractions as well as fraction size. In general the resistance developed fully in 48 hours after first hyperthermia, whereas it appeared to develop in 24 hours after the second treatment with a Ti of 2 days or after the third treatment with a Ti of 1 day. The resistance was less extensive for a large number of fractions with Ti of 2 days.

Effect of Whole-Body Hyperthermia on Cell Survival, Metastasis Frequency, and Host Immunity in Moderately and Weakly Immunogenic Murine Tumors

Resistance to subsequent hyperthermia as a result of prior heating was investigated using a spontaneous murine tumour implanted into the feet of C3H/Sed mice. Tumours were treated by immersing the tumour-bearing foot into a constant-temperature hot water bath set at 45.5 degrees C and were given single and split doses of heat. Response was assessed using a tumour-growth time assay. Three aspects of thermally-induced resistance were particularly considered: the time course of development and decay; the importance of the magnitude of the priming dose and the influence of the size of the tumour at the time of treatment. Substantial resistance was induced in this tumour by short priming doses at 45.5 degrees C, rising rapidly 1-2 days after the first treatment and then starting to decay. There was no significant difference in the kinetics of thermal resistance induced in tumours treated at 4mm and those treated at 8 mm in size, although the large tumours were more sensitive to single doses of heat. Increasing the magnitude of the priming dose of heat resulted in an increase in the magnitude of resistance to the second dose. The results of this study are compared with results of similar studies in this and other laboratories using murine normal tissues and cells in culture. Possible clinical implications are considered.