Bcl-2 in cancer cells was shown to be a potent indicator of 5-FU efficacy, but the protein in normal tissue cells appeared not to be a marker of 5-FU toxicity probably due to the functional alteration of Bcl-2 associated with cell senescence. Transfection analysis of Bcl-2-S and Bcl-2-AS into A549 lung cancer cells revealed that Bcl-2 suppressed cell death induced by 5-FU, and the gene expression level of Bcl-2 was closely correlated with the IC50 for 5-FU in 21 fresh human gastric tumor specimens. Such correlation could not be observed in a neonatal human foreskin fibroblast strain, MJ90 (HCA2), and 21 human normal tissues adjacent to tumors. Transfection analysis of Bcl-2-S and Bcl-2-AS into MJ90 cells showed that Bcl-2 correlated with the resistance to 5-FU in the transfectants at PDL60 as in A549 cells, but increased Bcl-2 in the PDL72 senescent transfectant did not cause an increase of the resistance to 5-FU. Cell aging was observed in MJ90 cells and Bcl-2 in the cells was found to decrease with the cell senescence. The senescent cells, however, were more resistant to 5-FU than the younger PDL60 cells having proliferation activity.