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

Cancer Gene Ther. 2001 Jan;8(1):3-8. doi: 10.1038/sj.cgt.7700265.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyclovir / administration & dosage
  • Acyclovir / therapeutic use*
  • Adenoviridae / genetics
  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Blotting, Western
  • Brain / pathology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / radiotherapy*
  • Combined Modality Therapy
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Female
  • Genetic Vectors / administration & dosage*
  • Glioma / genetics
  • Glioma / mortality
  • Glioma / radiotherapy*
  • Mutation
  • Neoplasm Transplantation
  • Radiation-Sensitizing Agents
  • Rats
  • Rats, Inbred F344
  • Simplexvirus / enzymology*
  • Survival Rate
  • Thymidine Kinase / genetics*
  • Transduction, Genetic
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / radiation effects

Substances

  • Antiviral Agents
  • Radiation-Sensitizing Agents
  • Thymidine Kinase
  • Acyclovir