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Cytosine deaminase/5-fluorocytosine exposure induces bystander and radiosensitization effects in hypoxic glioblastoma cells in vitro.

AbstractPURPOSE:
Treatment of glioblastoma (GBM) is limited by therapeutic ratio; therefore, successful therapy must be specifically cytotoxic to cancer cells. Hypoxic cells are ubiquitous in GBM, and resistant to radiation and chemotherapy, and, thus, are logical targets for gene therapy. In this study, we investigated whether cytosine deaminase (CD)/5-fluorocytosine (5-FC) enzyme/prodrug treatment induced a bystander effect (BE) and/or radiosensitization in hypoxic GBM cells.
METHODS AND MATERIALS:
We stably transfected cells with a gene construct consisting of the SV40 minimal promoter, nine copies of a hypoxia-responsive element, and the yeast CD gene. During hypoxia, a hypoxia-responsive element regulates expression of the CD gene and facilitates the conversion of 5-FC to 5-fluorouracil, a highly toxic antimetabolite. We used colony-forming efficiency (CFE) and immunofluorescence assays to assess for BE in co-cultures of CD-expressing clone cells and parent, pNeo- or green fluorescent protein-stably transfected GBM cells. We also investigated the radiosensitivity of CD clone cells treated with 5-FC under hypoxic conditions, and we used flow cytometry to investigate treatment-induced cell cycle changes.
RESULTS:
Both a large BE and radiosensitization occurred in GBM cells under hypoxic conditions. The magnitude of the BE depended on the number of transfected cells producing CD, the functionality of the CD, the administered concentration of 5-FC, and the sensitivity of cell type to 5-fluorouracil.
CONCLUSION:
Hypoxia-inducible CD/5-FC therapy in combination with radiation therapy shows both a pronounced BE and a radiosensitizing effect under hypoxic conditions.
AuthorsJennifer K Chen, Lily J Hu, Dongfang Wang, Kathleen R Lamborn, Dennis F Deen
JournalInternational journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 67 Issue 5 Pg. 1538-47 (Apr 01 2007) ISSN: 0360-3016 [Print] United States
PMID17394949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antimetabolites, Antineoplastic
  • Hypoxia-Inducible Factor 1
  • Prodrugs
  • Flucytosine
  • Cytosine Deaminase
Topics
  • Antimetabolites, Antineoplastic (therapeutic use)
  • Bystander Effect (drug effects)
  • Cell Hypoxia (drug effects, genetics)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cytosine Deaminase (genetics, therapeutic use)
  • Flucytosine (therapeutic use)
  • Gene Transfer Techniques
  • Glioblastoma (physiopathology, radiotherapy, therapy)
  • Humans
  • Hypoxia-Inducible Factor 1 (metabolism)
  • Prodrugs (therapeutic use)
  • Radiation Tolerance (drug effects, genetics)

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