Interaction between adriamycin cytotoxicity and hyperthermia: growth-phase-dependent thermal sensitization.

Abstract

Thermal sensitization of adriamycin cytotoxicity was studied in vitro and in vivo using tumour cells originated from a spontaneous mouse fibrosarcoma, FSa-II. The adriamycin dose-cell survival curve for exponentially growing cells was biphasic with the initial sensitive portion followed by a resistant tail. The survival curves determined in vitro as a function of treatment time at various temperatures were also biphasic. With increasing temperatures the initial portion became steeper and the resistant fraction decreased. At a temperature of 43 degrees C, which gives lethal damage to cells by itself, the cell survival decreased rapidly during the initial 30 min of treatment and became relatively constant for subsequent treatment times up to 180 min. The tumour response determined by the median tumour growth time for one-half of treated tumours to reach 1000 mm3 from the treatment day (35 mm3) indicated that the tumour response to adriamycin was independent of temperature. Hyperthermia at 43.5 degrees C for 60 min prolonged the tumour growth time without showing chemosensitization. The maximum drug dose used was 12 mg/kg that is < LD10 or the drug dose that kills animals with < 10% probability. The dose-response curves (tumour growth versus drug dose) showed identical slopes at room temperature, 41.5 and 43.5 degrees C. Further studies were conducted in vitro. Plateau phase cells were treated with graded adriamycin doses for 60 min at 37 degrees C, or with a constant adriamycin dose of 0.25 microgram/ml for various times at 37 or 43 degrees C. The dose-cell survival curves for both exponential and plateau phase cells were biphasic, but the plateau phase cells were more resistant to adriamycin at 37 degrees C than the exponential phase cells. The survival curve for plateau phase cells, determined as a function of treatment time, showed an initial shoulder followed by an exponential portion. Compared with the heat survival curve at 43 degrees C, the survival curve for the drug treatment at 43 degrees C was identical to that for the heat alone treatment for the first 60 min and then became steeper than the heat alone survival curve. These results suggest that adriamycin cytotoxicity may be enhanced at elevated temperatures only when tumours are treated for a prolonged time or possibly with a large drug dose.