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
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD / immunology
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Antigens, Differentiation, Myelomonocytic / immunology
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Carcinoma, Renal Cell / immunology
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / secondary
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Carcinoma, Renal Cell / therapy*
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Combined Modality Therapy
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Drug Carriers
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Female
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Genetic Engineering
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Genetic Therapy / methods*
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Immunotherapy / methods*
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Interleukin-2 / genetics*
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Interleukin-2 / metabolism
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Kidney Neoplasms / immunology
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / therapy*
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Leukocyte Common Antigens / immunology
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Lipids / administration & dosage
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Lung Neoplasms / immunology
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Lung Neoplasms / therapy
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Mice
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Microcirculation
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Neoplasms, Experimental
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Neovascularization, Pathologic
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Peptides, Cyclic / administration & dosage
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Polyethylene Glycols / administration & dosage
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Polyethyleneimine / administration & dosage
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Polyethyleneimine / analogs & derivatives
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Transfection / methods
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Vascular Endothelial Growth Factor Receptor-2 / genetics*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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CD68 antigen, human
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Drug Carriers
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Interleukin-2
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Lipids
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PEI-g-PEG-RGD
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Peptides, Cyclic
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poly(ethylenimine)-co-(N-(2-aminoethyl) ethyleneimin)-co-N-(N-cholesteryloxycarbonyl-(2-aminoethyl)ethylenimine)
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Polyethylene Glycols
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Polyethyleneimine
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Vascular Endothelial Growth Factor Receptor-2
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Leukocyte Common Antigens