THE DEVELOPMENT AND MAGNITUDE OF THERMOTOLERANCE DURING CHRONIC HYPERTHERMIA IN MURINE BONE-MARROW GRANULOCYTE-MACROPHAGE PROGENITORS .1.

Murine bone marrow granulocyte-macrophage progenitors (CFU-GM) are cap able of developing thermotolerance during exposure to temperatures <42 .5 degrees C. Bone marrow from the tibia and femora was heated to 40-4 2 degrees C (i.e. chronic hyperthermia), and challenged immediately wi th 15 min at 44 degrees C at regular intervals during treatment (step- up heating). CFU-GM were heated and cultured in McCoy's 5A medium + 15 % FBS (fetal bovine serum) and lung-conditioned medium (source of colo ny stimulating factor) in semisolid agar. The kinetics of thermotolera nce development and decay, and the magnitude of the thermotolerance du ring chronic heating with temperatures of 40-41.5 degrees C were simil ar. Survival increased rapidly to a maxima by approximately 120 min of hyperthermia (temperatures of 40-41.5 degrees C) and thereafter decre ased with a slope similar to the controls. Normalization for cell kill ing by chronic hyperthermia that occurred during 'step-up' heating per mitted analysis of thermotolerance in the surviving cells. The survivi ng fraction after 15 min at 44 degrees C, during incubation at 40, 41 and 41.5 degrees C increased from 0.13 to maxima of 0.56 +/- 0.04, 0.7 1 +/- 0.03 and 0.82 +/- 0.03 respectively, by 150 min and did not decr ease for up to 480 min during chronic hyperthermia The surviving fract ion after 15 min at 44 degrees C during incubation at 42 degrees C inc reased more slowly than during incubations at 40-41.5 degrees C. The s urvival of thermotolerant cells after exposure to 15 min at 44 degrees C during 42 degrees C chronic hyperthermia was maximal at 0.87 +/- 0. 08 by 120 min and then decreased after approximately 150 min of exposu re to 42 degrees C. The thermotolerance ratios (TTR's) were 4.0, 5.4, 6.7 and 6.9 for temperatures of 40, 41, 41.5 and 42 degrees C respecti vely. The results suggest that chronic hyperthermia temperatures (i.e. 40-42 degrees C) induce rapid thermotolerance development in CFU-GM d uring the thermal exposure and protect this normal marrow progenitor d uring whole body hyperthermia or ex vivo purging of leukaemic cells.