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Pepstatin, an Inhibitor of Leukokinin Formation and Ascitic Fluid Accumulation¹

Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Ascites fluid accumulation accompanying a mastocytoma or L1210 murine tumor is significantly retarded following the i.p. or s.c. injection of moderate quantities of pepstatin, a known acid protease inhibitor. No effect on cell count was noted by pepstatin treatment. The probable mechanism by which pepstatin acts is by inhibiting the enzymatic formation of chemical mediators known as leukokinins. These are pharmacologically active peptides having potent permeability characteristics previously described by this laboratory. Leukokinins are formed by cathepsin D-like enzymes present in the invading cells and in the ascites fluid acting on a protein substrate, leukokininogen, present in the ascites fluid. Pepstatin inhibits the action of these leukokinin-forming enzymes in vitro but has no effect on kallikreins (bradykinin-forming enzymes) in vitro. Human ascites fluid from a patient with ovarian carcinoma was found to have a pepstatin-inhibited, leukokinin-generating system, as does the mouse.

A "chemical mediator" theory is proposed for ascites formation which broadens the previously held theory of lymphatic blockage (Holm-Nielsen) and may explain the recent findings of Hirabayashi and Graham of increased plasma-ascites exchange in peritoneal carcinomatosis.

Pepstatin inhibition of chemical mediator formation may represent a new therapeutic approach to ascites fluid accumulation in neoplastic disease.

¹ Supported by USPHS Grants CA-13861 and GM-00438, and by Grant DT6 from the American Cancer Society. Preliminary reports of this work were presented at the 65th Meeting of the American Association for Cancer Research, Houston, Texas, 1974, and the International Symposium on Kinins, Ribeirao Preto, Brazil (8).

² Career Scientist of the Health Research Council of New York.

Received 6/11/74. Accepted 12/ 6/74.

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