Ischaemia induced cell death in tumors: Importance of temperature and pH

Abstract

Purpose : Increasing attention has focussed on the therapeutic potential of agents which can reduce tumor blood flow and induce ischaemia for long enough to result in tumor cell death. A confounding factor in this approach is the fact that the core temperature of superficial tumors reduces when the supplying blood flow is occluded and therefore protects the tumor cells from “metabolic” death. Consequently, we have tested the importance of tumor temperature on the relationship between vascular occlusion and cell death. Methods and Materials : The murine tumor CaNT used in this study was implanted subcutaneously in the dorsum. Total vascular occlusion was achieved by physically occluding the blood supply to the tumors for periods between 1 and 20 h. The mouse temperature was controlled by placing the whole body in a thermostatically controlled incubator maintained at 35°C. Tumor cell survival was assessed using an excision assay and by measuring the delay in growth of treated tumors. Measurement of tumor pH was achieved using microelectrodes. Results : The core temperature of unclamped tumors was approximately 33°C, but fell by about 5°C during vascular occlusion at room temperature. Tumor cell survival was decreased with increasing periods of vascular occlusion at room temperature, but a greater reduction in cell survival and correspondingly increased regrowth delay was observed when the tumor temperature was prevented from cooling below preocclusion values. The extracellular pH (pH e) fell during vascular occlusion and this reduction was greater when the tumor temperature was maintained at preocclusion values. This extracellular acidosis is expected to partly explain the observation of greater tumor cell death in those tumors whose temperature does not reduce during occlusion. Conclusion : The temperature of superficial tumors reduces in response to vascular occlusion. This may result in an underestimation of the cytotoxicity of agents which reduce tumor blood flow as the tumor cooling protects the cells from the acidosis that accumulates within the occluded tumor.