Inhibition of tumor growth by intramuscular injection of cDNA encoding tumor necrosis factor alpha coupled to NGR and RGD tumor-homing peptides.
The antitumor properties of tumor necrosis factor alpha (TNF) and its efficacy in selective destruction of tumor-associated vessels are well known. Besides the TNF protein, the TNF gene has been used for gene therapy of cancer and shown to induce antitumor responses both in animal models and in patients. We show here that the therapeutic properties of the TNF gene are improved by fusing the TNF sequence with those of peptides able to target tumor vessels, such as CNGRCG or ACDCRGDCFCG. Intramuscular administration of plasmid DNA encoding CNGRCG-TNF and ACDCRGDCFCG-TNF (pNGR-TNF and pRGD-TNF, respectively), but not plasmids encoding TNF (pTNF) or empty vector (pMock), inhibited the growth of subcutaneous murine B16F1 melanomas and RMA-T lymphomas implanted at sites distant from the site of plasmid injection. The combination of pNGR-TNF or pRGD-TNF with doxorubicin or melphalan induced stronger effects than single agents. These treatments induced antitumor effects without activating toxic or negative feedback mechanisms. In addition, pRGD-TNF increased the uptake of an antibody directed to a tumor-associated antigen. These results suggest that the therapeutic properties of NGR-TNF and RGD-TNF cDNAs are greater than those of TNF cDNA and provide the rationale for developing new gene therapy approaches based on vascular targeting with TNF coupled to tumor-homing peptides.
Zarovni
Natasa
N
Department of Biological and Technological Research, and Cancer Immunotherapy and Gene Therapy Program, San Raffaele H. Scientific Institute, 20132 Milan, Italy.
Monaco
Lucia
L
Corti
Angelo
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018076:DNA, Complementary / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects; D025461:Feedback, Physiological; D005260:Female; D015316:Genetic Therapy; D007273:Injections, Intramuscular; D016399:Lymphoma, T-Cell / Q000628:therapy*; D008546:Melanoma, Experimental / Q000628:therapy*; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D009842:Oligopeptides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin; D008558:Melphalan