Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization

Jaggi, J. S., Henke, E., Seshan, S. V., Kappel, B. J., Chattopadhyay, D., May, C., McDevitt, M. R., Nolan, D. J., Mittal, V., Benezra, R., Scheinberg, D. A. (March 2007) Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. PLoS ONE, 2 (3). e267. ISSN 19326203 (ISSN)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/17342201
DOI: 10.1371/journal.pone.0000267

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. Methodology and Principal Findings. Actinium-225 (225Ac)-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, 225Ac-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 225Ac-E4G10 treated 1tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following 225Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following 225Ac-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. © 2007 Jaggi et al.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies > alpha particle
diseases & disorders > cancer > angiogenesis
CSHL Authors:
Communities: CSHL labs > Mittal lab
Depositing User: CSHL Librarian
Date: 7 March 2007
Date Deposited: 14 Nov 2011 19:27
Last Modified: 27 Mar 2018 20:22
PMCID: PMC1801076
Related URLs:
URI: http://repository.cshl.edu/id/eprint/23050

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