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

Oncogene. 2001 Jul 19;20(32):4337-43. doi: 10.1038/sj.onc.1204508.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Cancer Vaccines / pharmacology*
  • Cell Division
  • Child
  • Humans
  • Injections, Intramuscular
  • Kidney / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Nude
  • Plasmids
  • Tissue Inhibitor of Metalloproteinases / genetics*
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Tissue Inhibitor of Metalloproteinases / pharmacology
  • Tumor Cells, Cultured
  • Vaccines, DNA / pharmacology*
  • Wilms Tumor / enzymology
  • Wilms Tumor / pathology
  • Wilms Tumor / therapy*

Substances

  • Cancer Vaccines
  • Tissue Inhibitor of Metalloproteinases
  • Vaccines, DNA
  • tissue inhibitor of metalloproteinase-4
  • Matrix Metalloproteinase 2