Effectiveness of 2',2'difluorodeoxycytidine (Gemcitabine) combined with hyperthermia in rat R-1 rhabdomyosarcoma in vitro and in vivo

Purpose : To investigate the schedule-dependency of 2 ,2 difluorodeoxycytidine (dFdC, Gemcitabine) combined with hyperthermia (HT), in vitro as well as in vivo . Materials and methods : Rat R-1 rhabdomyosarcoma cells were treated with various concentrations of dFdC for 70 min, 4h and 24h. After various time intervals HT (60min at 43 C) was applied. Cell survival was determined by clonogenic assays. Female Wag/Rij rats bearing R-1 tumours on the hind limbs were treated with dFdC (20mg/kg), with locally applied HT (60min at 43 C) or with a combined treatment using different time intervals (0, 24 and 48h). Tumour growth delay (TGD) and normal tissue toxicity were assessed. Results : With dFdC alone, significant cytotoxicity was observed after a 24h-exposure. Except for the 24h-exposure, HT reduced the cytotoxicity of dFdC in simultaneous applications. An enhanced cytotoxic effect was found when HT was applied 20h after a 4h-incubation with dFdC. In vivo , HT applied 48h after dFdC-administration resulted in potentiation of the effect of dFdC with respect to TGD without an increase in toxicity. Conclusions : The efficacy of dFdC combined with HT is schedule-dependent both in vitro and in vivo . The addition of HT enhances the effectiveness of dFdC in the R-1 tumour model.