CHEMOSENSITIVITY OF HUMAN-MALIGNANT GLIOMA - MODULATION BY P53 GENE-TRANSFER

Loss of wild-type p53 activity is one of the most common molecular abn ormalities in human cancers including malignant gliomas. The p53 statu s is also thought to modulate sensitivity to irradiation and chemother apy. Here, we studied the effect of a p53 gene transfer on the chemose nsitivity of three human glioma cell lines with different endogenous p 53 status (LN-229, wild-type; LN-18, mutant; LN-308, deleted), using t he murine temperature-sensitive p53 val(135) mutant. Expression of mut ant p53 enhanced proliferation of LN-308 cells but reduced proliferati on in the other cell lines. Expression of wild-type p53 caused reversi ble growth arrest of all cell lines but failed to induce apoptosis. Gr owth arrest induced by wild-type p53 was associated with strong induct ion of p21 expression. Strong induction of BAX expression and loss of BCL-2 expression, which are associated with p53-dependent apoptosis ra ther than growth arrest, were not observed. Wild-type p53 failed to se nsitize glioma cells to cytotoxic drugs including BCNU, cytarabine, do xorubicin, teniposide and vincristine. The combined effects of wild-ty pe p53 gene transfer and drug treatment were less than additive rather than synergistic, suggesting that the intracellular cascades activate d by p53 and chemotherapy are rebundant. Unexpectedly, forced expressi on of mutant p53 modulated drug sensitivity in that it enhanced the to xicity of some drugs but attenuated the effects of others. These effec ts may represent a dominant negative effect of mutant p53 in LN-229 ce lls 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-t ype 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 mal ignant glioma cells but is unlikely to induce clinically relevant sens itization to chemotherapy in these tumors.