We previously observed the inhibition of rumor growth and metastasis by PAI-1 (J.Clin.Invest. 96:2593,1995), and are presently studying the effect of another serine protease inhibitor, aprotinin. We observed that in addition to inhibition of metastasis, aprotinin produced massive necrosis in the primary tumors in the athymic mouse model of human prostate carcinoma (PC-3 cells). The cause of the necrosis was investigated by studying apoptosis under aprotinin treatment, both in vivo in the athymic mouse and in vitro in PC-3 cell cultures. The criteria for apoptosis were detection of DNA fragments(DNA laddering, nuclear TdT), presence of annexin V on cell surface and cell morphology. Primary tumors in aprotinin-treated mice showed increased apoptosis when compared with the control tumors. The addition of aprotinin to PC-3 cells in culture also increased apoptosis. On studying the conditioned media, we found that the aprotinin enhanced the uPA production while decreasing that of PAI-1. Northern blotting showed that mRNA of uPA increased and mRNA of PAI-1 decreased, with no change in that of uPA receptor. There is also no change in the cell count. Other serine protease inhibitors, FOY and ONO, also produced the same effects. These findings suggest that tumor growth is modulated both by uPA and by apoptosis and that the excessive apoptosis under the effect of aprotinin and the other serine protease inhibitors accounts in large part to the necrosis found in the tumors. These results open the way to a new approach in the understanding and the control of tumor growth.
|Original language||English (US)|
|Number of pages||1|
|Journal||Fibrinolysis and Proteolysis|
|Issue number||SUPPL. 3|
|State||Published - Dec 1 1997|
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