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

Abstract

Extracellular matrix (ECM) degrading matrix metalloproteinases (MMPs) lead to ECM turnover, a key event in cancer growth and progression. The tissue inhibitors of matrix metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use for cancer gene therapy. Here we report that systemic administration of naked TIMP-4 DNA significantly inhibited Wilms' tumor growth in nude mice. TIMP-4, whose expression was lost in Wilms' tumor, inhibited the growth of G401 Wilms' tumor cells at a concentration lower than those required for MMP inhibition. This inhibition was associated with internalization of exogenous recombinant TIMP-4. Electroporation-mediated intramuscular injection of TIMP-4 expression plasmid resulted in sustained plasma TIMP-4 levels and significant tumor suppression. Our data demonstrate a tumor suppressive effect of TIMP-4 against Wilms' tumor and the potential utility of intramuscular delivery of TIMP gene for treatment of kidney derived cancers.