Evaluating the Role of Serine Protease Inhibition in the Management of Tumor Micrometastases

October 1, 2003

Management of patients with neoplastic disease has shifted from searchand-destroy approaches employing radical surgery, chemotherapy,and radiotherapy to novel strategies that target specific molecular orgenetic characteristics or modify growth factors, angiogenesis, and cell-cell interactions.Attention has also been focused on modifying the production and function ofcertain enzymes pivotal to the genesis of disseminated disease.

Management of patients with neoplastic disease has shifted from searchand-destroy approaches employing radical surgery, chemotherapy,and radiotherapy to novel strategies that target specific molecular orgenetic characteristics or modify growth factors, angiogenesis, and cell-cell interactions.Attention has also been focused on modifying the production and function ofcertain enzymes pivotal to the genesis of disseminated disease.Serine proteases, the largest human protease gene family, mediate a variety ofevents relevant to fundamental processes of tumor invasion and metastasis.[1]Other protease types (eg, matrix metalloproteinases [MMPs]) have also beenimplicated in tumor-cell dissemination. The serine proteases are central to manyphysiologic processes because they initiate the activation and release of hemostatic,fibrinolytic, and inflammatory mediators.[2] Traditionally, modulation of serineproteases has focused on reducing blood loss and inflammation in the setting ofcardiovascular surgery. More recently, serine protease modulation has attractedincreasing interest because of the emerging evidence of the roles of these enzymesin cancer. The link between serine protease functions and cancer outcomes suggeststhat serine proteases might be a suitable target for therapeutic agents aimed atprevention of tumor progression and metastasis.Aprotinin is a broad-specificity serine protease inhibitor first isolated frombovine lung tissue in the 1930s. It acts on the interrelated inflammatory, coagulation,and fibrinolytic pathways to attenuate the systemic inflammatory response,inhibit hyperfibrinolysis, and promote hemostasis.[3-8] Pharmacologic interventionwith large doses of a serine protease inhibitor such as aprotinin (Trasylol) ispossible in humans, and it may benefit patients by reducing the transfusion burden;by inhibiting certain processes fundamental to an inflammatory response; and byinhibiting enzymes in the coagulation and fibrinolytic pathways that may be involved in the progression from local to disseminated disease. Each of these areaswill be discussed in turn in this special supplement to ONCOLOGY, which wasdeveloped from discussions held during a closed expert roundtable meeting inPasadena, California, in February 2003.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.