Recovery from Hyperthermic Damage and Development of Thermotolerance in Unfed Plateau-Phase Cells in Vitro2

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Abstract
The hyperthermic responses of unfed plateauphase cells and exponentially growing mouse lung cell L 1A2 heated to 42° C were compared in vitro. No difference in sensitivity to a single treatment up to 4 hours was found. However, in unfed cells the recovery from hyperthermic damage demonstrated during two-dose hyperthermic fractionation (1.5 hr at 42° C each) was reduced approximately 50% relative to that for cells in exponential growth. Preheating for 1.5 hours at 42° C induced thermal resistance to a second heat treatment at 42° C (thermotolerance). With a 10-hour interval, the degree of thermotolerance in unfed cells was reduced to approximately 55% compared to that for exponentially growing cells. Although the pH of the unfed culture was 6.8, adjustment of the pH to 7.2 either during the entire treatment, during the interval separating the two treatments, or during the second treatment resulted in a reduced development of thermotolerance similar to that observed in unfed cells treated without pH adjustment. Therefore, the reduced development of thermotolerance in unfed plateau-phase L1A2 cells was not due to an increased environmental acidity. The results in this study may indicate a way of increasing the therapeutic ratio with the use of fractionated hyperthermic schedules inasmuch as poorly vascularized parts of tumors may be characterized by nutritional depletion and a higher acidity as compared to the surrounding normal tissue.