title: In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP-II.
abstract: BACKGROUND
  Continued growth of solid tumors beyond a critical diameter is thought to require active angiogenic mechanisms, the inhibition of which carries therapeutic potential. We tested this strategy in an in vivo model of local tumor progression utilizing an agent with previously identified direct antiendothelial properties.
  
  
  METHODS
  Nonmetastatic C(6) glioma cells (10(6) per animal) were injected subcutaneously into the flank of nude mice with 6 to 8 animals per treatment group. Nodules at the injection site were measured at day 3 and every fourth day thereafter until day 15. Endothelial-monocyte-activating polypeptide II (EMAP-II), a substance known to induce endothelial cell apoptosis, was injected intraperitoneally daily from day 3 to day 15 at doses of 8 microg/kg (low dose) and 80 microg/kg (high dose). Tumor growth kinetics, histologic parameters, and tissue expression of VEGF were studied.
  
  
  RESULTS
  Tumor growth was significantly decreased in the EMAP-II-treated animals. Median tumor volume (in mm(3)) at day 15 was 2311 (Control), 727 (low dose), and 454 (high dose, P = 0.003). Median tumor weight (g) measured 1.8 (Control, 0.95 low dose), and 0.9 (high dose, P = 0.06). Median 12-day specific tumor growth rate (in mm(3)/day) per group was 191, 60, and 36 (P = 0.003). Decreased tumor growth after EMAP-II treatment correlated with significantly reduced microvessel counts, higher vascular thrombosis rate, and reduced tumor cell proliferation indices within the neoplastic tissue. Tumor levels, but not serum levels, of VEGF were significantly reduced after EMAP-II treatment. At the doses administered, there was no obvious systemic toxicity. EMAP-II had no direct cytotoxic or antiproliferative effects on tumor cells in vitro.
  
  
  CONCLUSIONS
  Daily administration of the antiendothelial agent EMAP-II led to a significant retardation of tumor growth, but no complete cancer abrogation. The findings support the hypothesis of an in vivo therapeutic benefit to antiangiogenic therapy with an agent that displays specific toxicity in vitro against endothelial cells. The mechanism of action remains unclear, but likely involves vascular thrombosis and leads to decreased VEGF expression.
authors.affiliation: Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, and The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. r.schwarz@umdnj.edu
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D016207:Cytokines / Q000008:administration & dosage*; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy*; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D009363:Neoplasm Proteins / Q000008:administration & dosage*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016601:RNA-Binding Proteins / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1