Radiation-inducible caspase-8 gene therapy for malignant brain tumors.
OBJECTIVE
Patients with malignant gliomas have a poor prognosis. To explore a novel and more effective approach for the treatment of patients with malignant gliomas, we designed a strategy that combines caspase-8 (CSP8) gene therapy and radiation treatment (RT). In addition, the specificity of the combined therapy was investigated to decrease the unpleasant effects experienced by the surrounding normal tissue.


METHODS
We constructed the plasmid pEGR-green fluorescence protein that included the radiation-inducible early growth response gene-1 (Egr-1) promoter and evaluated its characteristics. The pEGR-CSP8 was constructed and included the Egr-1 promoter and CSP8 complementary DNA. Assays that evaluated the apoptosis inducibility and cytotoxicity caused by CSP8 gene therapy combined with RT were performed using U251 and U87 glioma cells. The pEGR-CSP8 was transfected into the subcutaneous U251 glioma cells of nude mice by means of in vivo electroporation. The in vivo effects of CSP8 gene therapy combined with RT were evaluated.


RESULTS
The Egr-1 promoter yielded a better response with fractionated RT than with single-dose RT. In the assay of apoptosis inducibility and cytotoxicity, pEGR-CSP8 showed response for RT. The pEGR-CSP8 combined with RT is capable of inducing cell death effectively. In mice treated with pEGR-CSP8 and RT, apoptotic cells were detected in pathologic sections, and a significant difference was observed in tumor volumes.


CONCLUSIONS
Our results indicate that radiation-inducible gene therapy may have great potential because this can be spatially or temporally controlled by exogenous RT and is safe and specific.
Tsurushima
Hideo
H
Department of Biomedical Engineering, Medical School, Johns Hopkins University, Baltimore, MD, USA.
Yuan
Xuan
X
Dillehay
Larry E
LE
Leong
Kam W
KW
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D053181:Caspase 8 / Q000235:genetics* / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000627:therapeutic use; D018274:Electroporation / Q000379:methods; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D005910:Glioma / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010957:Plasmids / Q000235:genetics / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand
D051766:Early Growth Response Protein 1; D053221:TNF-Related Apoptosis-Inducing Ligand; D008156:Luciferases; D053181:Caspase 8