Transforming growth factor beta 1 (TGF-beta 1) is a potent growth inhibitor for many cell types, including tumor cells. We recently have reported the establishment and characterization of two human gastric scirrhous carcinoma cell lines, HSC-39 and HSC-43. Here we examined the effect of TGF-beta 1 on the growth of these lines as compared to five other human gastric adenocarcinoma cell lines. Proliferation of HSC-39 and HSC-43 cells was strongly inhibited by TGF-beta 1, whereas the other gastric adenocarcinoma cell lines were unresponsive to TGF-beta 1. Both HSC-39 and HSC-43 cells gradually lost viability following exposure to TGF-beta 1. This response was dose dependent up to 4 ng/ml. When TGF-beta 1 was removed, the cells failed to exhibit regrowth, indicating an irreversible growth-inhibitory effect of this agent, leading to cell death. DNA fragments were observed consisting of multimers of approximately 180 base pairs 24 h after TGF-beta 1 treatment. The chromatin condensation of each cell line was confirmed by Hoechst 33258 fluorochrome staining. Ultrastructurally, condensed and fragmented nuclei were observed in TGF-beta 1-treated cells. These features are generally associated with apoptotic processes. Both cell death and DNA fragmentation were partially inhibited by cycloheximide, suggesting the requirement for new protein synthesis. Our results suggest that TGF-beta 1 induces cell death in human gastric scirrhous carcinoma cells in vitro which is mediated by activation of a signal transduction pathway for apoptosis.