The potential role of aprotinin in the perioperative management of malignant tumors.

Aprotinin (Trasylol, Bayer Corporation, West Haven, CT), a nonspecific serine proteinase inhibitor, has been in clinical use since the early 1960s. It inhibits contact activation and fibrinolysis while preserving platelet function. In the United States aprotinin is used in cardiothoracic surgery for its beneficial effect on perioperative blood loss and transfusion requirements, reduction in explorative operations for bleeding, and inhibition of the systemic inflammatory response. In addition, aprotinin is effective in reducing intraoperative bleeding and reducing blood transfusion requirements in patients undergoing resections for meningioma, bladder carcinoma, and hepatic tumors, and in liver transplantation, orthopaedic procedures, and lumbar spine fusion. Less well known are reports that aprotinin may interfere with tumor growth and development of metastasis and may increase survival time after tumor resections. The role of aprotinin in tumor and metastasis inhibition is estimated to be three-fold. First, it is established that aprotinin reduces intraoperative blood loss and transfusion requirements. Second, its known antiinflammatory effect during the systemic inflammatory response syndrome is to prevent the sequestration of leukocytes within organs, and it suppresses the capacity of leukocytes to transmigrate through the vascular endothelium by interfering with expression of various adhesion molecules. The same integrin adhesion molecules used by normal leukocytes for traffic and localization in inflammation sites may be used by malignant cells for dissemination, so aprotinin is likely to interfere with tumor endothelial adhesion and transendothelial migration as well. Third, the ability of aprotinin to neutralize, to varying degrees, the action of several serine proteases, such as trypsin, chymotrypsin, and particularly the urokinase-type plasminogen activator (uPA) and kallikreins is important, because these proteases have been implicated in tumor progression and development of metastasis. In the pathogenesis of human malignancy, uPA mediates tumor cell growth, invasion, and metastatic dissemination. Evidence suggests a role for this system in several major human tumor types; tumor types in which the plasminogen activator-plasmin system has been implicated as a mechanism for tumor progression include breast, uterine cervix, endometrium, and ovary; stomach, colon, and rectum; bladder, kidney, liver, and pancreas; brain (glioma); nonsmall cell lung; and melanoma. Also, uPA facilitates the provisional matrix needed to promote endothelial cell adhesion, migration, proliferation, and survival in the formation of new blood vessels. Animal-model systems collectively point to the causal involvement of uPA in the metastatic process. This relationship between tumor cell uPA expression and tumor progression has been studied in animal models of breast, colon, lung, prostate, and ovarian cancer, and in human tumor cells in vitro. The kallikreins, a group of serine proteases, are associated with many disease processes, including cancer, inflammation, hypertension, renal disease, and pancreatitis. The association between kallikrein genes and human disease is summarized in Table 1. All members of the human kallikrein gene family encode for serine proteases and are involved in contact activation of the coagulation pathway. Manipulation of kallikreins may be a possible means of interfering with tumor progression. Prostate-specific antigen (PSA; human kallikrein 3) is the best-studied kallikrein, with a focus on its implication in prostate cancer. Serum PSA is generally elevated in patients with prostate cancer, although other published data suggest that PSA may be a tumor suppressor. Patients with breast tumors that produce PSA have a worse prognosis than patients whose tumors do not proNo competing interests declared.