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Suppression of human glioma growth by adenovirus-mediated Rb gene transfer

From the Departments of Neuro-Oncology (Drs. Fueyo, Gomez-Manzano, Yung, Alemany, Levin, and Kyritsis), Head and Neck Surgery (Dr. Liu), Pathology(Dr. Bruner), and Neurosurgery (Drs. Chintala and Rao), The University of Texas M.D. Anderson Cancer Center, Houston.

Address correspondence and reprint requests to Dr. Juan Fueyo, Department of Neuro-Oncology, Box 316, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.

Objective: This study was conducted to obtain evidence that restoration of the retinoblastoma protein function may have therapeutic application for gliomas.

Background: The development of glioblastoma multiforme involves progressive inactivation of several tumor suppressor genes. Abnormalities of the retinoblastoma tumor suppressor gene are found in the majority of cancers, including at least 30% of malignant gliomas. No final evidence has been produced about the role of Rb in suppressing glioma growth.

Methods: To address this question, the Ad5CMV-Rb adenovirus carrying a 3.2-kb cDNA of the Rb gene was constructed. Expression of the exogenous protein was assessed by immunoblot and immunohistochemistry analyses. Growth curve assays were used to evaluate the effect of the Rb protein on glioma cell growth. Flow-cytometry analyses were used to analyze the phenotype of the cell cycle after the transfer of Rb. Human glioma xenografts implanted subcutaneously in nude mice were used for the tumorigenicity assay.

Results: After the transfer of Rb, 80% of the treated cells expressed high levels of the retinoblastoma protein for at least 7 days. Within 5 days of treatment, the cells lost the neoplastic morphology and showed marked growth suppression. The majority of the Rb-expressing cells were arrested in the G₁ phase of the cell cycle. In addition, the restoration of the retinoblastoma activity rendered the human glioma cells unable to form tumors in nude mice.

Conclusions: These findings provide direct evidence that inactivation of the retinoblastoma protein is a critical event in gliomas, and suggest that the restoration of wild-type retinoblastoma activity in these tumors may have therapeutic utility.

Presented in part at the 48th annual meeting of the American Academy of Neurology, San Francisco, CA, March 1996.

Supported by a Biomedical Research Support Grant (8-0040383) from the U.T.M.D. Anderson Cancer Center.

Received June 12, 1997. Accepted in final form January 10, 1998.

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