title: NGR-TNF, a novel vascular-targeting agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells.
abstract: BACKGROUND
  Administration of certain chemotherapy drugs at the maximum tolerated dose, vascular-disrupting agents (VDAs) and irradiation can induce mobilisation and tumour homing of proangiogenic bone marrow-derived cells (BMDCs). Increases in cytokines and chemokines contribute to such mobilisation that eventually promotes tumour (re)growth. NGR-TNF is a vascular-targeting agent in advanced clinical development, coupling the CNGRCG angiogenic vessel-homing peptide with tumour necrosis factor-alpha (TNF). We investigated whether NGR-TNF mobilises host BMDCs and growth factors.
  
  
  METHODS
  Blood was obtained from Lewis lung carcinoma and 4T1 tumour-bearing mice at different time points following NGR-TNF, VDA or anti-VEGFR2/flk-1 antibody treatment. Levels of circulating growth factors were assessed by ELISAs. BMDCs were characterised by FACS. Circulating endothelial progenitor cells were defined as CD45(-)/CD13(+)/flk-1(+)/CD117(+)/7AAD(-), Tie2-expressing monocytes as CD45(+)/CD11b(+)/Tie2(+) and myeloid-derived suppressor cells as CD45(+)/CD11b(+)/Gr1(+) cells.
  
  
  RESULTS
  NGR-TNF decreases tumour blood vessel density-inducing apoptosis of tumour and tumour endothelial cells. Unlike VDAs, or high-dose NGR-TNF, lower doses of NGR-TNF, comparable to those used in clinical trials, neither mobilise nor recruit to the tumour site proangiogenic BMDCs or induce host growth factors.
  
  
  CONCLUSIONS
  Low-dose NGR-TNF exerts antitumour activity without inducing proangiogenic host responses, conceivably important for preventing/overcoming resistance and designing combination therapeutic strategies.
authors.affiliation: MolMed SpA, Via Olgettina 58, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Di Matteo
authors.forename: C
authors.initials: C
authors.lastname: Hackl
authors.forename: C
authors.initials: C
authors.lastname: Jedeszko
authors.forename: B
authors.initials: B
authors.lastname: Valentinis
authors.forename: C
authors.initials: C
authors.lastname: Bordignon
authors.forename: C
authors.initials: C
authors.lastname: Traversari
authors.forename: R S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: G-P
authors.initials: GP
authors.lastname: Rizzardi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; C464840:tumor Necrosis Factor-alpha, CNGRC fusion protein, mouse