title: Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization.
abstract: BACKGROUND
  Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature.
  
  
  RESULTS
  Actinium-225 ((225)Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, (225)Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in (225)Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following (225)Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following (225)Ac-E4G10 therapy.
  
  
  CONCLUSIONS
  The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Singh Jaggi
authors.forename: Erik
authors.initials: E
authors.lastname: Henke
authors.forename: Surya V
authors.initials: SV
authors.lastname: Seshan
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Kappel
authors.forename: Debjit
authors.initials: D
authors.lastname: Chattopadhyay
authors.forename: Chad
authors.initials: C
authors.lastname: May
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
authors.forename: Daniel
authors.initials: D
authors.lastname: Nolan
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000186:Actinium / Q000627:therapeutic use; D000512:Alpha Particles / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000528:radiation effects; D015902:Gamma Cameras; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control* / Q000532:radiotherapy; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D007205:Indium Radioisotopes; D000186:Actinium