The matrix metalloproteinases and their inhibitors in the treatment of pancreatic cancer.
Matrix metalloproteinases (MMPs) are a family of zinc-containing proteolytic enzymes that break down extracellular matrix proteins (ECM) in physiological and pathological conditions. Disruption in the tight control of MMP metabolism occurs in cancer, resulting in excessive destruction of the ECM, neovascularization, tumor spread and metastases. Recent studies have shown that overexpression of MMPs is associated with poor prognosis. Several MMP inhibitors have been developed and preclinical trials have confirmed a reduction in tumor spread and metastases. Marimastat is a broad spectrum inhibitor, and recent published results shows the drug is well tolerated in patients with advanced cancer. Phase II studies which have used marimistat alone or in combination with other cytotoxic agents, have produced encouraging results with improved survival. Phase III trials are now underway for the use of marimastat in advanced pancreatic cancer and as an adjuvant therapy in patients following resection of pancreatic cancer.
Department of Surgery, Royal Liverpool University Hospital, UK.
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Jones
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Ghaneh
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Humphreys
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Neoptolemos
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005109:Extracellular Matrix; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D015533:Transcriptional Activation
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D008666:Metalloendopeptidases