Radiosensitization of human glioma cells in vitro and in vivo with acyclovir and mutant HSV-TK75 expressed from adenovirus.
OBJECTIVE
We recently reported that an adenovirus-expressing mutant HSV-TK75 (AdCMV-TK75) radiosensitized rat syngeneic gliomas in combination with low concentrations of acyclovir (ACV) much more effectively than a virus expressing wild-type herpes simplex virus thymidine kinase (HSV-TK). In this report we have examined whether similar radiosensitizing effects are also seen with human glioma cells in vitro and in vivo.


METHODS
Human U87 MG glioma cells were transduced with AdCMV-TK75 and exposed to ACV followed by single-dose irradiation and colony-forming survival assays. Similarly, U87 MG xenografts were infused with AdCMV-TK75 or Adbetagal control virus, followed by ACV administration and fractionated irradiation. Therapeutic efficacy was monitored by tumor growth.


RESULTS
U87 MG cells transduced with AdCMV-TK75 were significantly more sensitive to ACV (3 microM) than cells transduced with either wild-type HSV-TK or control virus. To determine whether human cells also demonstrate improved radiosensitization similar to that seen with rat glioma cells and tumors, we transduced U87 MG cells with either AdCMV-TK75, AdCMV-TK, expressing wild-type HSV-TK, or Adbetagal and then treated the cells with 3 microM of ACV. Cells transduced with AdCMV-TK75 were significantly more radiosensitive (dose enhancement ratio [D(37)]: 2.6) by colony-forming survival assay than cells transduced with either AdCMV-TK or Adbetagal. Furthermore, we found that U87 MG xenografts infused with AdCMV-TK75 by slow positive pressure infusion were more radiosensitive after administration of ACV than tumors infused with Adbetagal. A more dramatic result was achieved when fractionated irradiation was carried out concurrently with ACV administration, in which case AdCMV-TK75-treated tumors did not grow at all.


CONCLUSIONS
These results demonstrate that transduction of human glioma cells in vitro and infusion of xenografts in vivo with AdCMV-TK75 and treatment with concentrations of ACV that can be achieved in vivo produce similar radiosensitization, as previously reported with rat glioma cells and intracerebral syngeneic tumors. In addition, concurrent treatment with ACV and radiation therapy is more efficient than when ACV is administered before radiation therapy.
Rosenberg
Elizabeth
E
Department of Radiation Oncology, Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0058, USA.
Hawkins
William
W
Holmes
Matthew
M
Amir
Cyrus
C
Schmidt-Ullrich
Rupert K
RK
Lin
Peck Sun
PS
Valerie
Kristoffer
K
D000212:Acyclovir / Q000627:therapeutic use*; D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005910:Glioma / Q000188:drug therapy / Q000532:radiotherapy* / Q000821:virology; D006564:Herpesviridae / Q000201:enzymology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011836:Radiation Tolerance; D011853:Radiobiology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D000998:Antiviral Agents; D013937:Thymidine Kinase; D000212:Acyclovir