Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization.
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 p...
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doaj-03198722d0234e46a520b7fbf0417fa02020-11-25T00:24:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032007-03-0123e26710.1371/journal.pone.0000267Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization.Jaspreet Singh JaggiErik HenkeSurya V SeshanBarry J KappelDebjit ChattopadhyayChad MayMichael R McDevittDaniel NolanVivek MittalRobert BenezraDavid A ScheinbergAbnormal 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.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.The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy.http://europepmc.org/articles/PMC1801076?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jaspreet Singh Jaggi Erik Henke Surya V Seshan Barry J Kappel Debjit Chattopadhyay Chad May Michael R McDevitt Daniel Nolan Vivek Mittal Robert Benezra David A Scheinberg |
spellingShingle |
Jaspreet Singh Jaggi Erik Henke Surya V Seshan Barry J Kappel Debjit Chattopadhyay Chad May Michael R McDevitt Daniel Nolan Vivek Mittal Robert Benezra David A Scheinberg Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. PLoS ONE |
author_facet |
Jaspreet Singh Jaggi Erik Henke Surya V Seshan Barry J Kappel Debjit Chattopadhyay Chad May Michael R McDevitt Daniel Nolan Vivek Mittal Robert Benezra David A Scheinberg |
author_sort |
Jaspreet Singh Jaggi |
title |
Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. |
title_short |
Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. |
title_full |
Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. |
title_fullStr |
Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. |
title_full_unstemmed |
Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. |
title_sort |
selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2007-03-01 |
description |
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.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.The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy. |
url |
http://europepmc.org/articles/PMC1801076?pdf=render |
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