A rational approach to the specific chemotherapy of pancreatitis

Abstract

Oedematous pancreatitis is pancreatic acinar cell damage with leakage into the peritoneal cavity and circulation of the inactive zymogens of digestive enzymes and active amylase and lipase. Pancreatic oedema and intra-abdominal fat necrosis occur. Necrotising pancreatitis is pancreatic acinar cell damage accompanied by the specific conversion of trypsinogens to trypsins, at a rate, and on a scale, sufficient to overwhelm local defences. Rapid release of the whole spectrum of activated pancreatic enzymes leads to necrosis of parts of the pancreas and blood vessels, and the disseminated enzyme-mediated damage which characterises the molecular pathology of the established severe disease. Chronic pancreatitis, although less well understood, is also associated with trypsinogen activation within the gland. Two mechanisms have emerged as initiators of trypsinogen activation, lysosomal cathepsins and bile-borne enterokinase. Chemotherapeutic strategies against disease initiation include preparation of synthetic enterokinase and Cathepsin B inhibitors. Chemotherapeutic strategies against second-stage mediation of multi-organ damage in the disease, include oligopeptide or organic functionalities with novel catalytic site-directed moieties (such as fluoromethyl ketones) suitable for in vivo use and the specific inhibition of the relevant range of enzymes in complex with alpha 2-macroglobulin. Interference with pancreatic enzyme biosynthesis using proteolysis-resistant constructs mimicking receptor-binding domains of inhibitor peptide hormones as well as inhibitors of pancreatic signal peptidase are promising additional chemotherapeutic approaches worthy of active investigation.