Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization Journal Article
| Authors: | Jaggi, J. S.; Henke, E.; Seshan, S. V.; Kappel, B. J.; Chattopadhyay, D.; May, C.; McDevitt, M. R.; Nolan, D.; Mittal, V.; Benezra, R.; Scheinberg, D. A. |
| Article 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. 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. |
| Keywords: | immunohistochemistry; cancer survival; controlled study; unclassified drug; drug efficacy; drug potentiation; drug safety; monotherapy; nonhuman; paclitaxel; cancer radiotherapy; prostate specific antigen; mouse; animal tissue; mus; apoptosis; tumor volume; animal experiment; animal model; combination chemotherapy; endothelium cell; cancer inhibition; survival time; drug distribution; drug uptake; vascular endothelium; tumor cell; hematopoietic stem cell; tumor vascularization; antiangiogenic activity; drug dose sequence; prostate carcinoma; pericyte; vascular endothelial cadherin; alpha radiation; actinium 225; e 4g10 ac 225 |
| Journal Title: | PLoS ONE |
| Volume: | 2 |
| Issue: | 3 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2007-03-01 |
| Start Page: | e267 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0000267 |
| PROVIDER: | scopus |
| PMCID: | PMC1801076 |
| PUBMED: | 17342201 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 9" - "Export Date: 17 November 2011" - "Source: Scopus" |
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