title: Peptide-mediated targeting of cytokines to tumor vasculature: the NGR-hTNF example.
abstract: A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.
authors.affiliation: Tumor Biology and Vascular Targeting Unit, Division of Molecular Oncology, San Raffaele Scientific Institute, via Olgettina 58, 20132, Milan, Italy, corti.angelo@hsr.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Gilda
authors.initials: G
authors.lastname: Rossoni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marcucci
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gregorc
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016207:Cytokines; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human