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) expressed from an adenovirus (AdCMV-TK75) radiosensitized rat RT2 glioma cells significantly better than wild type HSV-TK (AdCMV-TK) in combination with acyclovir (ACV). To examine whether a similar improvement could also be observed in vivo, we tested these viruses in a syngeneic rat glioma tumor model (RT2/Fischer 344). First, we demonstrate that treatment with AdCMV-TK and ACV significantly radiosensitizes implanted gliomas and roughly doubles the mean survival time to 37 days, compared to 20 days for control animals implanted with Adbetagal-transduced cells (P<.02). Second, it was important to first examine the effect of AdCMV-TK75 and ACV on survival without any irradiation. We found that AdCMV-TK75 appeared to sensitize gliomas more efficiently than AdCMV-TK, although this difference was not significant ( P= .19 ). Third, and most importantly, in combined HSV-TK, ACV and irradiation experiments, we demonstrate that AdCMV-TK75 is superior over AdCMV-TK and significantly (P<.005) prolonged the survival of treated animals. Our results suggest that AdCMV-TK75 is far more efficient than AdCMV-TK in radiosensitizing rat glioma when administered in combination with ACV.
Valerie
K
K
Department of Radiation Oncology, Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0058, USA. kvalerie@hsc.vcu.edu
Hawkins
W
W
Farnsworth
J
J
Schmidt-Ullrich
R
R
Lin
P S
PS
Amir
C
C
Feden
J
J
D000212:Acyclovir / Q000008:administration & dosage / Q000627:therapeutic use*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage*; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D009154:Mutation; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents; D051381:Rats; D011916:Rats, Inbred F344; D018139:Simplexvirus / Q000201:enzymology*; D015996:Survival Rate; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D000998:Antiviral Agents; D011838:Radiation-Sensitizing Agents; D013937:Thymidine Kinase; D000212:Acyclovir