Improved radiosensitization of rat glioma cells with adenovirus-expressed mutant herpes simplex virus-thymidine kinase in combination with acyclovir (original) (raw)

Cancer Gene Therapy volume 7, pages 879–884 (2000)Cite this article

Abstract

Adenovirus expressing herpes simplex virus-thymidine kinase (HSV-TK) sensitizes internal rat glioma cells to radiation in combination with acyclovir (ACV). However, relatively high concentrations of ACV (>10 μM) are required to obtain significant radiosensitization. Serum levels rarely reach more than the lower micromolar range, preventing the full use of this genetic approach to radiosensitize cells in vivo. To better use the lower concentrations of ACV available in sera, we constructed an adenovirus expressing a mutant HSV-TK (HSV-TK(75)) isolated for its ∼20 times greater sensitivity to ACV than wild-type (wt) HSV-TK. We demonstrate that rat RT2 glioma cells infected with adenovirus AdCMV-TK(75) and exposed to either ACV or ganciclovir become more sensitive to lower concentrations (1–3 μM) of the drugs compared with cells infected with AdCMV-TK(wt), which expresses wt HSV-TK. Most importantly, the RT2 cells become more sensitive to low doses (2–4 Gy) of 60Co radiation than cells infected with an adenovirus expressing wt HSV-TK. This sensitization is accompanied by an increased rate of apoptosis. In summary, we show that infection of rat glioma cells with an adenovirus expressing a mutant HSV-TK sensitizes the cells to low doses of radiation after exposure to ACV at lower concentrations than those required for wt HSV-TK. This finding suggests that this mutant adenovirus may improve the in vivo efficacy of HSV-TK-based cancer gene therapy approaches.

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Authors and Affiliations

  1. Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, Virginia
    Kristoffer Valerie, David Brust, Julie Farnsworth, Cyrus Amir, Mohiuddin M Taher, Chad Hershey & Jeffrey Feden
  2. Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, Virginia
    Kristoffer Valerie, Julie Farnsworth & Cyrus Amir
  3. Department of Biostatistics, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, Virginia
    Cyrus Amir

Authors

  1. Kristoffer Valerie
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  2. David Brust
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  3. Julie Farnsworth
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  4. Cyrus Amir
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  5. Mohiuddin M Taher
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  6. Chad Hershey
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  7. Jeffrey Feden
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Corresponding author

Correspondence toKristoffer Valerie.

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Valerie, K., Brust, D., Farnsworth, J. et al. Improved radiosensitization of rat glioma cells with adenovirus-expressed mutant herpes simplex virus-thymidine kinase in combination with acyclovir.Cancer Gene Ther 7, 879–884 (2000). https://doi.org/10.1038/sj.cgt.7700185

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