INTERACTION BETWEEN ADRIAMYCIN CYTOTOXICITY AND HYPERTHERMIA - GROWTH-PHASE-DEPENDENT THERMAL SENSITIZATION

Thermal sensitization of adriamycin cytotoxicity was studied in vitro and in vivo using tumour cells originated from a spontaneous mouse fib rosarcoma, FSa-II. The adriamycin dose-cell survival curve for exponen tially growing cells was biphasic with the initial sensitive portion f ollowed by a resistant tail. The survival curves determined in vitro a s a function of treatment time at various temperatures were also bipha sic. With increasing temperatures the initial portion became steeper a nd the resistant fraction decreased. At a temperature of 43 degrees C, which gives lethal damage to cells by itself, the cell survival decre ased rapidly during the initial 30 min of treatment and became relativ ely constant for subsequent treatment times up to 180 min. The tumour response determined by the median tumour growth time for one-half of t reated tumours to reach 1000 mm(3) from the treatment day (35 mm(3)) i ndicated that the tumour response to adriamycin was independent of tem perature. Hyperthermia at 43.5 degrees C for 60 min prolonged the tumo ur growth time without showing chemosensitization. The maximum drug do se used was 12 mg/kg that is <LD(10) or the drug dose that kills anima ls with <10% probability. The dose-response curves (tumour growth vers us drug dose) showed identical slopes at room temperature, 41.5 and 43 .5 degrees C. Further studies were conducted in vitro. Plateau phase c ells were treated with graded adriamycin doses for 60 min at 37 degree s C, or with a constant adriamycin dose of 0.25 mu g/ml for various ti mes at 37 or 43 degrees C. The dose-cell survival curves for both expo nential and plateau phase cells were biphasic, but the plateau phase c ells were more resistant to adriamycin at 37 degrees C than the expone ntial phase cells. The survival curve for plateau phase cells, determi ned as a function of treatment time, showed an initial shoulder follow ed 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 eleva ted temperatures only when tumours are treated for a prolonged time or possibly with a large drug dose.