Inhibition of Wilms' tumor growth by intramuscular administration of tissue inhibitor of metalloproteinases-4 plasmid DNA

Extracellular matrix (ECM) degrading matrix metalloproteinases (MMPs) lead to ECM turnover, a key event in cancer growth and progression. The tissue i nhibitors of matrix metalloproteinases (TIMPs) Limit the activity of MMPs, which suggests their use for cancer gene therapy. Here we report that syste mic administration of naked TIMP-4 DNA significantly inhibited Wilms' tumor growth in nude mice. TIMP-4, whose expression was lost in Wilms' tumor, in hibited the growth of G401 Wilms' tumor tells at a concentration lower than those required for MMP inhibition. This inhibition was associated with int ernalization of exogenous recombinant TIMP-4, Electroporation-mediated intr amuscular injection of TIMP-4 expression plasmid resulted in sustained plas ma TIMP-4 levels and significant tumor suppression. Our data demonstrate a tumor suppressive effect of TIMP-4 against Wilms' tumor and the potential u tility of intramuscular delivery of TIMP gene for treatment of kidney deriv ed cancers.