Synergistic damage of tumor vessels with ultra low-dose endothelial-monocyte activating polypeptide-II and neovasculature-targeted tumor necrosis factor-alpha.
High-dose endothelial-monocyte activating polypeptide II (EMAP-II), a tumor-derived antiangiogenic cytokine, can sensitize tumor vasculature to the damaging activity of high-dose tumor necrosis factor (TNF)-alpha. However, this combination cannot be used for systemic treatment of patients because of prohibitive toxicity. We have found that this limitation can be overcome by combining a TNF-targeting strategy with the use of ultra low-dose EMAP-II. Coadministration of 0.1 ng of EMAP-II and 0.1 ng of CNGRCG-TNF (NGR-TNF), a peptide-TNF conjugate able to target tumor blood vessels, inhibited lymphoma and melanoma growth in mice, with no evidence of toxicity. This drug combination induced endothelial cell apoptosis in vivo and, at later time points, caused reduction of vessel density and massive apoptosis of tumor cells. Ligand-directed targeting of TNF was critical because the combination of nontargeted TNF with EMAP-II was inactive in these murine models. The synergism was progressively lost when the dose of EMAP-II was increased in the nanogram to microgram range, supporting the concept that the use of low-dose EMAP-II is critical. Studies on the mechanism of this paradoxical behavior showed that EMAP-II doses >1 ng induce the release of soluble TNF receptor 1 in circulation, a strong counter-regulatory inhibitor of TNF. Tumor vascular targeting with extremely low amounts of these cytokines may represent a new strategy for cancer treatment.
Crippa
Luca
L
Department of Oncology, Cancer Immunotherapy-Gene Therapy Program and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Gasparri
Anna
A
Sacchi
Angelina
A
Ferrero
Elisabetta
E
Curnis
Flavio
F
Corti
Angelo
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C077219:small inducible cytokine subfamily E, member 1; C464840:tumor Necrosis Factor-alpha, CNGRC fusion protein, mouse; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human