p53 gene status modulates the chemosensitivity of non-small cell lung cancer cells

This study examined the effects of p53 gene status on DNA damage-induced ce ll death and chemosensitivity to various chemotherapeutic agents in non-sma ll cell lung cancer (NSCLC) cells. A mutant p53 gene was introduced into ce lls carrying the wild-type p53 gene and also vice verse to introduce the wi ld-type p53 gene into cells carrying the mutant p53 gene. Chemosensitivity and DNA damage-induced apoptosis in these cells were then examined. This st udy included five cell lines, NCl-H1437, NCl-H727, NCl-H441 and NCl-H1299 w hich carry a mutant p53 gene and NCl-H460 which carries a wild-type p53 gen e. Mutant p53-carrying cells were transfected with the wild-type p53 gene, while mutant p53 genes were introduced into NCl-H460 cells. These p53 genes were individually mutated at amino acid residues 143, 175, 248 and 273. Th e representative cell line NCl-H1437 cells transfected with wild-type p53 g ene (H1437/wtp53) showed a dramatic increase in susceptibility to three ant icancer agents (7-fold to cisplatin, 21-fold to etoposide, and 20-fold to c amptothecin) compared to untransfected or neotransfected H1437 cells. An in crease in chemosensitivity was also observed in wild-type p53 transfectants of H727, H441, H1299 cells. The results: of chemosensitivity were consiste nt with the observations on apoptotic cell death. H1437/wtp53 cells, but no t H1437 parental cells, exhibited a characteristic feature of apoptotic cel l death that generated oligonucleosomal-sized DNA fragments. In contrast, l ass of chemosensitivity and lack of p53-mediated DNA degradation in respons e to anticancer agents were observed in H460 cells transfected with mutant p53. These observations suggest that the increase in chemosensitivity was a ttributable to wild-type p53 mediation of the process of apoptosis. In addi tion, our results also suggest that p53 gene status modulates the extent of chemosensitivity and the induction of apoptosis by different anticancer ag ents in NSCLC cells. Copyright (C) 2000 National Science Council, ROC and S . Karger AG. Basel.