Multiple genetic alterations, including inactivation of the p53 and RB genes and loss of heterozygosity on chromosome 3p, occur commonly in small cell lung carcinoma (SCLC). To assess the biological significance of p53 inactivation in the development of SCLC, tetracycline (Tc)-inducible p53 expression plasmids were introduced into a SCLC cell line, N417, in which the p53 gene as well as the RB gene was inactivated. In the absence (induced) of Tc, cells transfected with the wild-type p53 gene formed colonies in 29-58% of those with a mutant p53 gene. However, wild-type p53 genes were expressed in 0 of 43 transfectants, whereas mutant p53 genes were expressed in 75% (36/48) of the transfectants, suggesting that the growth of SCLC cells was suppressed by the expression of the wild-type p53 gene. Thus, wild-type p53-inducible clones were further established by transfection in the presence (repressed) of Tc. The in vitro growth was significantly suppressed by the induction of wild-type p53 expression, and apoptosis but not G1 arrest was observed within 24 h of p53 induction. These results strongly suggest that the restoration of the p53 function is sufficient to suppress the growth of SCLC cells in which other genetic alterations remain uncorrected, and that growth suppression by p53 is due to induction of apoptosis but not due to induction of G1 arrest through the RB pathway.