Time- and sequence-dependent responses to cisplatin and radiation in the rat kidney

The influence of time interval and sequence between administration of cisplatin and a radiation dose was studied in the rat kidney. A dose of 10.5 Gy X-rays was given to both kidneys, preceded or followed by a single dose of cisplatin. Two separate experiments were performed. In the first experiment 6.0 mg/kg cisplatin was given, in the second experiment the drug dose was 5.5 mg/kg. A range of time intervals was introduced between administration of drug and radiation, from 7 to 1 days, 12 to 1 h, and 30 to 0 min. Control animals received either modality alone, or were left untreated. Cisplatin alone caused tubular function to decrease very quickly and to remain permanently altered. Changes in glomerular function were only detected after 30 weeks following the higher drug dose. X-rays alone caused measurable alterations in both glomerular and tubular function after 16 weeks. In the combined treatment the influence of time and sequence was significant. If cisplatin was given at 7 to 1 days before X-rays the effect of time was minimal. Administration of cisplatin 12 h to 15 min before irradiation resulted in an increase of radiation damage with decreasing time interval. Total damage sharply decreased when both modalities were given at the same time, and decreased further with increasing time between irradiation and drug administration. It is suggested that in the tubular cells free cisplatin or one of its hydrolysis products may interact with radiation-induced damage, e.g. by interference with repair of sublethal or potentially lethal damage.