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Published on: June 23, 2023
Radiation-inducible caspase-8 gene therapy for malignant brain tumors
Hideo Tsurushima1, Xuan Yuan, Larry E Dillehay
1Department of Biomedical Engineering, Medical School, Johns Hopkins University, Baltimore, MD, USA.
Purpose:
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 And Materials:
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.
Insights
This study combined caspase-8 (CSP8) gene therapy with radiation treatment (RT) for malignant gliomas. The novel approach showed effectiveness in inducing cell death and reducing tumor volume in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Malignant gliomas present a significant challenge due to poor patient prognosis.
- Conventional treatments often have limitations in efficacy and specificity.
Purpose of the Study:
- To investigate a novel combination therapy for malignant gliomas using caspase-8 (CSP8) gene therapy and radiation treatment (RT).
- To assess the specificity and efficacy of this combined approach in targeting glioma cells while minimizing damage to surrounding normal tissues.
Main Methods:
- Construction of a radiation-inducible plasmid (pEGR-CSP8) utilizing the early growth response gene-1 (Egr-1) promoter.
- Evaluation of apoptosis induction and cytotoxicity in U251 and U87 glioma cells in vitro.
- In vivo transfection of pEGR-CSP8 into U251 glioma cells in nude mice via electroporation, followed by RT.
Main Results:
- The Egr-1 promoter demonstrated enhanced response with fractionated RT compared to single-dose RT.
- pEGR-CSP8 combined with RT effectively induced apoptosis and cytotoxicity in glioma cells.
- Significant reduction in tumor volumes and detection of apoptotic cells were observed in vivo.
Conclusions:
- Radiation-inducible gene therapy holds significant potential for malignant glioma treatment.
- This approach offers spatial and temporal control via external RT, ensuring safety and specificity.
