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Intracerebral adenovirus-mediated p53 tumor suppressor gene therapy for experimental human glioma
H Li1, M Alonso-Vanegas, M A Colicos
1Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Abstract:
Malignant gliomas of astrocytic origin are good candidates for gene therapy because they have proven incurable with conventional treatments. Although mutation or inactivation of the p53 tumor suppressor gene occurs at early stages in gliomas and is associated with tumor progression, many tumors including high-grade glioblastoma multiforme carry a functionally intact p53 gene. To evaluate the effectiveness of p53-based therapy in glioma cells that contain endogenous wild-type p53, a clinically relevant model of malignant human glioma was established in athymic nu/nu mice. Intracerebral, rapidly growing tumors were produced by stereotactic injection of the human U87 MG glioma cell line that had been genetically modified for tracking purposes to express the Escherichia coli lacZ gene encoding beta-galactosidase. Overexpression of the p53 gene by adenovirus-mediated delivery into the tumor mass resulted in rapid cell death with the eradication of beta-galactosidase-expressing glioma cells through apoptosis. In long-term experiments, the survival of mice treated with the p53 adenoviral recombinant was significantly longer than that of mice that had received control adenoviral recombinant. During the observation period of 1 year, a complete cure was achieved in 27% of animals after a single injection of p53 adenoviral recombinant, and 38% of the animals were tumor free in the group receiving multiple injections of p53 adenoviral recombinant into a larger tumor mass. These experiments demonstrate that overexpression of p53 in gliomas, even in the presence of endogenous functional wildtype p53, leads to efficient elimination of tumor cells. These results point to the potential therapeutic usefulness of this approach for all astrocytic brain tumors.
Insights
Gene therapy using p53 adenoviral vectors shows promise for treating malignant gliomas. Overexpressing p53 effectively eliminated glioma cells, improving survival rates in mice with wild-type p53 tumors.
Area of Science:
- Oncology
- Gene Therapy
- Neuro-oncology
Background:
- Malignant gliomas are difficult to treat with conventional therapies.
- The p53 tumor suppressor gene is crucial in glioma progression, but many tumors retain functional wild-type p53.
- Gene therapy offers a potential alternative for gliomas with intact p53.
Purpose of the Study:
- To assess the efficacy of p53 gene therapy in glioma cells with endogenous wild-type p53.
- To establish a clinically relevant model for evaluating p53-based gene therapy in malignant human glioma.
Main Methods:
- A human U87 MG glioma cell line expressing the lacZ gene was stereotactically injected into athymic nu/nu mice.
- Adenovirus-mediated delivery of the p53 gene was used to overexpress p53 within the tumor mass.
- Tumor growth, cell death (apoptosis), and animal survival were monitored over a 1-year period.
Main Results:
- Overexpression of p53 via adenovirus led to rapid glioma cell death through apoptosis.
- Mice treated with p53 adenoviral recombinant showed significantly longer survival compared to controls.
- Complete cures were observed in 27% of mice after a single p53 gene therapy injection, and 38% were tumor-free with multiple injections.
Conclusions:
- p53 gene overexpression is an effective strategy for eliminating glioma cells, even those with functional wild-type p53.
- Adenovirus-mediated p53 gene therapy demonstrates significant therapeutic potential for astrocytic brain tumors.
- This approach offers a promising avenue for treating gliomas resistant to conventional treatments.