Non-viral delivery of interleukin-2 and soluble Flk-1 inhibits metastatic and primary tumor growth in renal cell carcinoma

Gene Ther. 2007 Oct;14(19):1399-405. doi: 10.1038/sj.gt.3302999. Epub 2007 Jul 26.

Abstract

Treatments for renal cell carcinoma, while promising, are still limited by toxicity and cost. In the hopes of finding a novel compound or combination, we developed a plasmid containing the genes for interleukin-2 (IL-2) and soluble vascular endothelial growth factor receptor 2 (msFlk1). The plasmid, p2CMVIL2/msFlk1, demonstrated similar in vitro transgene expression of IL-2 or msFlk1 compared to their single-agent counterparts. Subcutaneous tumor growth was significantly inhibited in the p2CMVIL2/msFlk1 group when delivered locally by the non-viral water soluble polymer, WSLP and exhibited a 50% increase in survival over glucose and single-agent controls. In vivo experimentation demonstrated that WSLP/msFlk1 decreased microvessel density in pCMVmsFlk1 and p2CMVIL2/msFlk1 treated groups. Furthermore, tumor-infiltrating lymphocytes expressing CD45RO and CD68 were increased within the tumor microenvironment upon p2CMVIL2/msFlk1 treatment. To determine the effects of p2CMVIL2/msFlk1 in an experimental RENCA lung metastases model, therapeutic DNA was delivered systemically following complexation with the angiogenic endothelial-targeting polymer PEI-g-PEG-RGD. The p2CMVIL2/msFlk1 treatment significantly reduced metastases by 56% over single-agent therapy and increased survival proportions by 50% over all groups. Our work clearly demonstrates that non-viral delivery of p2CMVIL2/msFlk1 can inhibit RENCA growth in a synergistic manner and may represent a new treatment for renal carcinoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, Differentiation, Myelomonocytic / immunology
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / secondary
  • Carcinoma, Renal Cell / therapy*
  • Combined Modality Therapy
  • Drug Carriers
  • Female
  • Genetic Engineering
  • Genetic Therapy / methods*
  • Immunotherapy / methods*
  • Interleukin-2 / genetics*
  • Interleukin-2 / metabolism
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / therapy*
  • Leukocyte Common Antigens / immunology
  • Lipids / administration & dosage
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Mice
  • Microcirculation
  • Neoplasms, Experimental
  • Neovascularization, Pathologic
  • Peptides, Cyclic / administration & dosage
  • Polyethylene Glycols / administration & dosage
  • Polyethyleneimine / administration & dosage
  • Polyethyleneimine / analogs & derivatives
  • Transfection / methods
  • Vascular Endothelial Growth Factor Receptor-2 / genetics*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Drug Carriers
  • Interleukin-2
  • Lipids
  • PEI-g-PEG-RGD
  • Peptides, Cyclic
  • poly(ethylenimine)-co-(N-(2-aminoethyl) ethyleneimin)-co-N-(N-cholesteryloxycarbonyl-(2-aminoethyl)ethylenimine)
  • Polyethylene Glycols
  • Polyethyleneimine
  • Vascular Endothelial Growth Factor Receptor-2
  • Leukocyte Common Antigens