Angiogenesis involves multiple steps including proliferation and migration of endothelial cells. In the present study, we determined the effect of inostamycin (an inhibitor of phosphatidylinositol synthesis) on vascular endothelial growth factor (VEGF)-induced proliferation and migration of human umbilical vein endothelial cells (HUVECs). Inostamycin significantly attenuated both VEGF-induced proliferation and migration of HUVECs. Inostamycin inhibited activation of mitogen-activated kinases (ERK and p38) and elevation of cyclin D1 induced by VEGF. These data suggest that inostamycin reduced both proliferation and migration of HUVECs by targeting ERK-cyclin D1 and p38, respectively.

Apoptosis is a mode of cell death characterized by distinct morphological features and DNA fragmentation. The program that leads to apoptosis has been considered to be predominantly extranuclear, and a signal transduction pathway to the nucleus exists during apoptosis, while characteristic events occur in the nucleus. As for radiation-induced apoptosis, the signal transduction pathway remains unclear, especially the sites where the primary effect of radiation occurs. In this study, we demonstrate that a cytoplasmic extract prepared from irradiated cells has the ability to cause DNA fragmentation and that caspase-3 is activated in this extract. Normal nuclei of HeLa S3 cells were added to a cytoplasmic extract made from HL60 cells which had been irradiated with 30 Gy of 137Cs gamma rays and were incubated. Agarose gel electrophoresis of the added nuclei showed a characteristic DNA laddering pattern. This reaction was blocked by a caspase-3 inhibitor but not by an ICE inhibitor. These observations suggest that a signal transduction pathway from an unknown target of gamma radiation may exist upstream of caspase-3 during radiation-induced apoptosis.

Twelve patients with mucosal melanoma in the head and neck were treated at Yokohama city University from 1975 to 1994. The sex distribution was 5 male and 7 female, and the age ranged from 40 to 79 year-old. The

The signal transduction pathway involved in radiation-induced apoptosis remains unclear, especially as regards the site at which the primary effect of radiation occurs. In this study, we demonstrate that cytochrome c may be released from mitochondria into the cytosol after irradiation, but that direct irradiation of isolated mitochondria induces no elevation of cytochrome c release. These observations suggest that cytochrome c and mitochondria may be involved in the radiationinduced apoptotic pathway, but mitochondria might not be a target of radiation, and that a signal transduction pathway from an unknown target might exist upstream of mitochondria during radiation-induced apoptosis.