EXPRESSION OF THE P53 TUMOR-SUPPRESSOR GENE-PRODUCT IS A DETERMINANT OF CHEMOSENSITIVITY

Many cytotoxic agents act by causing DNA damage, and the p53 tumour su ppressor gene is known to be involved in the cellular response to DNA damage. Since inactivation of p53 is common in many tumours, we wonder ed if this would affect the sensitivity of cancer cells to cytotoxic a gents. We have shown that this is indeed the case in transformed mouse cell lines with and without a mutated p53 gene; p53 ''knockout'' mous e fibroblasts; and normal human skin fibroblasts treated with an anti- sense p53 oligonucleotide. In addition, we have demonstrated a correla tion between p53 protein expression in human breast cancer specimens a nd their chemosensitivity. The results show that inactivation or mutat ion of p53 renders cells more sensitive to those cytotoxic drugs whose primary mechanism of action is DNA damage. (C) 1994 Academic Press, I nc.