Pepstatin, an inhibitor of leukokinin formation and ascitic fluid accumulation

Abstract

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 inhigiting the enzymatic formation of chemical mediators known as leukokinins. These are pharmoacologically active peptiedes 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. Pestatin inhibits the action of these leukokinin-forming enzymes invitro but has no effect on kallikreins (bradykinin-forming enzymes) in vitro. Human ascites fluid from a patient with ovarian carcioma was found to have a paepstatin-inhibited, leukokinin-generating system, as does the mouse. A 'chemical mediator' theory is proposed for ascites fromation 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 carcionmatosis. Pepstatin inhibition of chemical mediator formation may represent a new therapeutic approach to ascites fluid accumulation in neoplastic disease.