Substantially improved in vivo radiosensitization of rat glioma with mutant HSV-TK and acyclovir

We recently demonstrated in vitro that a mutant HSV-TK (mutant 75) expresse d from an adenovirus (AdCMV-TK75) radiosensitized rat RT2 glioma cells sign ificantly better than wild type HSV-TK (AdCMV-TK) in combination with acycl ovir (ACV). To examine whether a similar improvement could also be observed in vivo, we tested these viruses in a syngeneic rat glioma tumor model (RT 2/Fischer 344). First, we demonstrate that treatment with AdCMV-TK and ACV significantly radiosensitizes implanted gliomas and roughly doubles the mea n survival time to 37 days, compared to 20 days for control animals implant ed with Ad beta gal-transduced cells (P<.02). Second, it was important to f irst examine the effect of AdCMV-TK75 and ACV on survival without any irrad iation. We found that AdCMV-TK75 appeared to sensitize gliomas more efficie ntly than AdCMV-TK, although this difference was not significant (P=.19). T hird, and most importantly, in combined HSV-TK, ACV and irradiation experim ents, we demonstrate that AdCMV-TK75 is superior over AdCMV-TK and signific antly (P<.005) prolonged the survival of treated animals. Our results sugge st that AdCMV-TK75 is far more efficient than AdCMV-TK in radiosensitizing rat glioma when administered in combination with ACV.