Matrix metalloproteinase inhibitors: present achievements and future prospects.
Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes. Several synthetic matrix metalloproteinase inhibitors (MMPIs) are currently being developed. Preclinical studies are promising as they suggest inhibition of several steps in the metastatic process. Marimastat is the first MMPI to enter comparative phase III trials after early clinical trials established the safety profile. Clinical trials will need to be specifically designed to optimally evaluate the therapeutic potential of this novel class of cytostatic drugs. Safety studies should consider the markedly different toxicity profile and determine the range of biologically active dosage, while efficacy studies should be performed in selected clinical settings with appropriate end-points. We review the present achievements in preclinical and clinical studies with MMPIs, discuss specific considerations for appropriate study design and reflect on the future prospects of this novel class of agents.
Denis
L J
LJ
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands.
Verweij
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; C100342:marimastat; D008666:Metalloendopeptidases