Development of thermotolerance during fractionated hyperthermia in a solid tumor in vivo.

The effect of 43.5 degrees water bath heating on a C3H mammary carcinoma inoculated into the foot of BALB/c x DBA F1 (hereafter called CD2F1 mice was investigated. A single heat treatment resulted in a linear dose-response relationship between heating time and tumor growth time (i.e., the time for tumors to reach 5 times the initial volume of the first treatment day). Recovery from hyperthermic damage, demonstrated by two-dose fractionation experiments (30 min + 60 min at 43.5 degrees), increased with increasing fractionation interval and reached its maximum at a 16-hr interval. Preheating for 30 min at 43.5 degrees induced thermal resistance to a second heat treatment at 43.5 degrees (thermotolerance) which was evidenced by a decrease in the slope of the dose-response curves. This thermotolerance gradually increased with increasing interval and reached a maximum at a 16-hr interval with a thermotolerance ratio of 5.2. Subsequently, the thermotolerance gradually decayed and completely disappeared at a 120-hr interval. No detectable repair of hyperthermic damage was found in this tumor. In principle, there data confirm the observations on thermotolerance reported previously for cell cultures in vitro and for several normal tissues in vivo.