Effectiveness of 2',2'difluorodeoxycytidine (Gemcitabine) combined with hyperthermia in rat R-1 rhabdomyosarcoma in vitro and in vivo.
OBJECTIVE
To investigate the schedule-dependency of 2',2'difluorodeoxycytidine (dFdC, Gemcitabine) combined with hyperthermia (HT), in vitro as well as in vivo.


METHODS
Rat R-1 rhabdomyosarcoma cells were treated with various concentrations of dFdC for 70 min, 4 h and 24 h. After various time intervals HT (60 min at 43 degrees 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 (20 mg/kg), with locally applied HT (60 min at 43 degrees C) or with a combined treatment using different time intervals (0, 24 and 48 h). Tumour growth delay (TGD) and normal tissue toxicity were assessed.


RESULTS
With dFdC alone, significant cytotoxicity was observed after a 24 h-exposure. Except for the 24 h-exposure, HT reduced the cytotoxicity of dFdC in simultaneous applications. An enhanced cytotoxic effect was found when HT was applied 20 h after a 4 h-incubation with dFdC. In vivo, HT applied 48 h 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.
Van Bree
C
C
Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, The Netherlands. c.vanbree@amc.uva.nl
Beumer
C
C
Rodermond
H M
HM
Haveman
J
J
Bakker
P J
PJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002455:Cell Division; D002470:Cell Survival; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006979:Hyperthermia, Induced / Q000009:adverse effects; D051381:Rats; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine