Sensitization of rat glioblastoma multiforme to cisplatin in vivo following restoration of wild-type p53 function.
ABSTRACT To study the combined potential of wild-type p53 gene transfer and administration of cisplatin for the treatment of glioblastoma multiforme, the authors used the 9L rat glioblastoma cell line, which expresses a mutant p53.
Stable expression of wild-type p53 in 9L cells was achieved by transfection of the cells with a wild-type p53-expressing plasmid (pCEP4p53). The resultant cell line, 9LpCEP4p53, was found to be more sensitive to cisplatin treatment in vitro than control (9LpCEP4) cells. The in vitro growth rates of control cells and wild-type p53-modified cells were similar in the absence of cisplatin. Fischer 344 rats were implanted intracerebrally with 9LpCEP4p53 cells and intraperitoneally administered 4 mg/kg cisplatin weekly for 7 weeks. These animals survived significantly longer than animals that were implanted with 9LpCEP4p53 cells but were given no cisplatin treatment. In contrast, concurrent cisplatin treatment provided no benefit for animals implanted with 9LpCEP4 cells. Tumors that developed in animals that had been implanted with 9LpCEP4p53 cells and treated with cisplatin had lost expression of wild-type p53, indicating a correlation between expression of wild-type p53 and cisplatin sensitivity in vivo.
The findings of this study suggest that p53-based gene therapy in combination with cisplatin-based chemotherapy may be superior to single-modality treatment in dealing with glioblastoma multiforme.
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ABSTRACT: Gliomas are the most common tumors originating in the brain. Most gliomas are malignant. They are the cause of death in almost all patients who harbor them. Even tumors that are originally relatively benign histologically, usually evolve into more malignant tumors and prove life-threatening. Current treatments for malignant gliomas include surgery,radiotherapy, chemotherapy, and immunotherapy, either singly or in combination. Transient control is possible in many cases, yet recurrence is the rule.Possible reasons for tumor recurrence include failure to extirpate all infiltrating tumor cells, tumor resistance to chemotherapy and radiotherapy, and decreased immune response in the brain.
- European Journal of Cancer - EUR J CANCER. 01/1999; 35(14):2039-2057.
Article: Gene therapy for cancer1European Journal of Cancer 12/1999; 35(14):2039–2057. · 4.82 Impact Factor