title: Chromogranin A restricts drug penetration and limits the ability of NGR-TNF to enhance chemotherapeutic efficacy.
abstract: NGR-TNF is a derivative of TNF-α that targets tumor blood vessels and enhances penetration of chemotherapeutic drugs. Because of this property, NGR-TNF is being tested in combination with chemotherapy in various phase II and III clinical trials. Here we report that chromogranin A (CgA), a protein present in variable amounts in the blood of normal subjects and cancer patients, inhibits the synergism of NGR-TNF with doxorubicin and melphalan in mouse models of lymphoma and melanoma. Pathophysiologically relevant levels of circulating CgA blocked NGR-TNF-induced drug penetration by enhancing endothelial barrier function and reducing drug extravasation in tumors. Mechanistic investigations done in endothelial cell monolayers in vitro showed that CgA inhibited phosphorylation of p38 MAP kinase, disassembly of VE-cadherin-dependent adherence junctions, paracellular macromolecule transport, and NGR-TNF-induced drug permeability. In this system, the N-terminal fragment of CgA known as vasostatin-1 also inhibited drug penetration and NGR-TNF synergism. Together, our results suggest that increased levels of circulating CgA and its fragments, as it may occur in certain cancer patients with nonneuroendocrine tumors, may reduce drug delivery to tumor cells particularly as induced by NGR-TNF. Measuring CgA and its fragments may assist the selection of patients that can respond better to NGR-TNF/chemotherapy combinations in clinical trials.
authors.affiliation: Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Dondossola
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gasparri
authors.forename: Barbara
authors.initials: B
authors.lastname: Colombo
authors.forename: Angelina
authors.initials: A
authors.lastname: Sacchi
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002463:Cell Membrane Permeability; D053379:Chromogranin A / Q000378:metabolism* / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008558:Melphalan / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D053379:Chromogranin A; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human; D004317:Doxorubicin; D008558:Melphalan