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

Kristoffer Valerie, David Brust, Julie Farnsworth, Cyrus Amir, Mohiuddin M. Taher, Chad Hershey, Jeffrey Feden

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)879-884
Number of pages6
JournalCancer gene therapy
Volume7
Issue number6
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

Fingerprint

Acyclovir
Thymidine Kinase
Simplexvirus
Adenoviridae
Glioma
Radiation Dosage
Ganciclovir
Neoplasm Genes
Serum
Genetic Therapy
Radiation
Apoptosis
Infection
Pharmaceutical Preparations

Keywords

  • Apoptosis
  • Cancer gene therapy
  • Fischer 344 rat
  • RT2 glioma cells
  • Suicide gene

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Improved radiosensitization of rat glioma cells with adenovirus- expressed mutant herpes simplex virus-thymidine kinase in combination with acyclovir. / Valerie, Kristoffer; Brust, David; Farnsworth, Julie; Amir, Cyrus; Taher, Mohiuddin M.; Hershey, Chad; Feden, Jeffrey.

In: Cancer gene therapy, Vol. 7, No. 6, 01.01.2000, p. 879-884.

Research output: Contribution to journalArticle

Valerie, Kristoffer ; Brust, David ; Farnsworth, Julie ; Amir, Cyrus ; Taher, Mohiuddin M. ; Hershey, Chad ; Feden, Jeffrey. / Improved radiosensitization of rat glioma cells with adenovirus- expressed mutant herpes simplex virus-thymidine kinase in combination with acyclovir. In: Cancer gene therapy. 2000 ; Vol. 7, No. 6. pp. 879-884.
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