Figure 5
Induction of apoptosis in the tumor mass in nude mice by cimetidine. A, tumor appearance in mice treated with cimetidine or saline. Bar, 10 mm. A, left, saline was administered to the mice. A, middle, 10-4 M cimetidine was administered to the mice. Regression of HSG tumor mass was observed. A, right, 10-2 M cimetidine was administered to the mice. The HSG tumor mass was completely resolved. B, histopathological findings revealed that the tumor mass was composed of several nodular tumors. The small nodes were composed of large round tumor cell cords clearly demarcated from the stroma. Inflammatory small round cell infiltration was found in the stroma. C, at 10-4 M cimetidine, apoptotic cell death was markedly observed by TUNEL in 4 of 10 mice (40%) in which HSG tumor masses had formed. Significant morphologic changes, including shrinkage of cytoplasm, fragmented nuclei and release of apoptotic vesicles in HSG tumor mass, were also indicated by arrows (right). D, at the highest dose of cimetidine (daily doses of 10-2 M), the HSG tumor mass was completely resolved when 1 × 106 HSG cells were injected subcutaneously. E, the expression of NCAM in HSG tumor mass was decreased by cimetidine in a dose-dependent fashion. Each column and bar represents the mean ± S.E.M. of three independent experiments.