Abstract
Tumours regrowing after irradiation may respond differently to chemo-hyperthermia as compared to non- irradiated tumours. In this study, the efficacy of combined treatment of previously irradiated tumors with mitoxantrone and local hyperthermia (HT) was investigated. Rat R-1 tumours were irradiated with dose fractions of 5Gy X-rays applied on 4 consecutive days. Animals were retreated with mitoxantrone (5mg/kg i.p.), HT (1 h at 43 degrees C) or mitoxantrone + HT (3-h interval) on day 9 after the start of irradiation when tumour volumes were decreasing, or on day 16 when tumour volumes were increasing again. Pharmacokinetics were studied in relation to tumor cell survival and tumour growth delay. No Ht=induced changes in the pharmacokinetics of mitoxantrone were observed. The data on clonogenic survival correlated well with these findings and combined treatment were not more effective than mitoxantrone alone. In the treatment schedule applied, HT did not induce pharmacokinetic changes in irradiated tumours leading to an enhanced cytotoxicity of mitoxantrone. The HT- enhanced effectiveness of the drug observed in non- irradiated tumours is much less in pre-irradiated tumours. Responses of regrowing tumours to combined chemo- hyperthermia depend in a complex way on the stage of regrowth and on the treatment schedule.