J Korean Med Sci.  2000 Jun;15(3):315-322. 10.3346/jkms.2000.15.3.315.

Potentials and limitations of adenovirus-p53 gene therapy for brain tumors

• Hong YK
• Joe YA
• Yang YJ
• Lee KS
• Son BC
• Jeun SS
• Chung DS
• Cho KK
• Park CK
• Kim MC
• Kim HK
• Yung WK
• Kang JK

• KMID: 1128631
• DOI: http://doi.org/10.3346/jkms.2000.15.3.315

Abstract

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.

Keyword

Genes, p53; Gene Therapy; Glioma; Brain Neoplasms; Adenoviridae

MeSH Terms

Adenoviruses, Human
Animal
Brain Neoplasms/therapy*
Cell Division
Gene Therapy*
Genetic Vectors
Glioma/therapy*
Human
Mice
Mice, Nude
Protein p53/physiology
Protein p53/genetics*
Rats
Tumor Cells, Cultured