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Chemosensitivity of human malignant glioma: modulation by p53 gene transfer
M Trepel1, P Groscurth, U Malipiero
1Department of Neurology, University of Tübingen, Medical School, Germany.
Abstract:
Loss of wild-type p53 activity is one of the most common molecular abnormalities in human cancers including malignant gliomas. The p53 status is also thought to modulate sensitivity to irradiation and chemotherapy. Here, we studied the effect of a p53 gene transfer on the chemosensitivity of three human glioma cell lines with different endogenous p53 status (LN-229, wild-type; LN-18, mutant; LN-308, deleted), using the murine temperature-sensitive p53 val135 mutant. Expression of mutant p53 enhanced proliferation of LN-308 cells but reduced proliferation in the other cell lines. Expression of wild-type p53 caused reversible growth arrest of all cell lines but failed to induce apoptosis. Growth arrest induced by wild-type p53 was associated with strong induction of p21 expression. Strong induction of BAX expression and loss of BCL-2 expression, which are associated with p53-dependent apoptosis rather than growth arrest, were not observed. Wild-type p53 failed to sensitize glioma cells to cytotoxic drugs including BCNU, cytarabine, doxorubicin, teniposide and vincristine. The combined effects of wild-type p53 gene transfer and drug treatment were less than additive rather than synergistic, suggesting that the intracellular cascades activated by p53 and chemotherapy are redundant. Unexpectedly, forced expression of mutant p53 modulated drug sensitivity in that it enhanced the toxicity of some drugs but attenuated the effects of others. These effects may represent a dominant negative effect of mutant p53 in LN-229 cells which have wild-type p53 activity but must be considered a gain of function-type effect in the other two cell lines which have no wild-type p53 activity. Importantly, no clear-cut pattern emerged among the three cell lines studied. We conclude that somatic gene therapy based on the reintroduction of p53 will limit the proliferation of human malignant glioma cells but is unlikely to induce clinically relevant sensitization to chemotherapy in these tumors.
Insights
p53 gene therapy can slow glioma cell growth but does not enhance chemotherapy sensitivity. Wild-type p53 induces growth arrest, not apoptosis, and its effects are redundant with chemotherapy, limiting clinical potential.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Loss of wild-type p53 is common in human cancers, including malignant gliomas.
- p53 status influences sensitivity to radiation and chemotherapy.
- Understanding p53's role is crucial for developing effective glioma treatments.
Purpose of the Study:
- To investigate the effect of p53 gene transfer on the chemosensitivity of human glioma cell lines.
- To analyze the impact of wild-type and mutant p53 expression on glioma cell proliferation and drug response.
- To determine the potential of p53 reintroduction as a therapeutic strategy for malignant gliomas.
Main Methods:
- Utilized three human glioma cell lines with distinct endogenous p53 statuses (wild-type, mutant, deleted).
- Employed a murine temperature-sensitive p53 val135 mutant for gene transfer studies.
- Assessed cell proliferation, apoptosis, p21 and BAX/BCL-2 expression, and chemosensitivity to various drugs (BCNU, cytarabine, doxorubicin, teniposide, vincristine).
Main Results:
- Wild-type p53 expression induced reversible growth arrest in all cell lines, associated with p21 upregulation but not apoptosis.
- Mutant p53 expression differentially affected proliferation, enhancing it in one cell line while reducing it in others.
- Wild-type p53 gene transfer did not sensitize glioma cells to chemotherapy; combined effects were additive, not synergistic.
- Forced mutant p53 expression modulated drug sensitivity, with varied effects on toxicity.
- No clear sensitization pattern emerged across the studied cell lines.
Conclusions:
- Somatic gene therapy with p53 can inhibit malignant glioma cell proliferation.
- p53 reintroduction is unlikely to induce clinically significant sensitization to chemotherapy in these tumors.
- The intracellular pathways activated by p53 and chemotherapy appear to be redundant.