Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.

These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. En...

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Autores principales:	Branka Stancevic, Nira Varda-Bloom, Jin Cheng, John D Fuller, Jimmy A Rotolo, Mónica García-Barros, Regina Feldman, Shyam Rao, Ralph R Weichselbaum, Dror Harats, Adriana Haimovitz-Friedman, Zvi Fuks, Michel Sadelain, Richard Kolesnick
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/385d5a0a20444620b152eb931564bc92
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spelling	oai:doaj.org-article:385d5a0a20444620b152eb931564bc922021-11-18T09:01:34ZAdenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.1932-620310.1371/journal.pone.0069025https://doaj.org/article/385d5a0a20444620b152eb931564bc922013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23936314/?tool=EBIhttps://doaj.org/toc/1932-6203These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x), and a hypoxia-inducible dual-binding HIF-2α-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x)-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x)-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x)-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.Branka StancevicNira Varda-BloomJin ChengJohn D FullerJimmy A RotoloMónica García-BarrosRegina FeldmanShyam RaoRalph R WeichselbaumDror HaratsAdriana Haimovitz-FriedmanZvi FuksMichel SadelainRichard KolesnickPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e69025 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Branka Stancevic Nira Varda-Bloom Jin Cheng John D Fuller Jimmy A Rotolo Mónica García-Barros Regina Feldman Shyam Rao Ralph R Weichselbaum Dror Harats Adriana Haimovitz-Friedman Zvi Fuks Michel Sadelain Richard Kolesnick Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
description	These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x), and a hypoxia-inducible dual-binding HIF-2α-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x)-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x)-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x)-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.
format	article
author	Branka Stancevic Nira Varda-Bloom Jin Cheng John D Fuller Jimmy A Rotolo Mónica García-Barros Regina Feldman Shyam Rao Ralph R Weichselbaum Dror Harats Adriana Haimovitz-Friedman Zvi Fuks Michel Sadelain Richard Kolesnick
author_facet	Branka Stancevic Nira Varda-Bloom Jin Cheng John D Fuller Jimmy A Rotolo Mónica García-Barros Regina Feldman Shyam Rao Ralph R Weichselbaum Dror Harats Adriana Haimovitz-Friedman Zvi Fuks Michel Sadelain Richard Kolesnick
author_sort	Branka Stancevic
title	Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
title_short	Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
title_full	Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
title_fullStr	Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
title_full_unstemmed	Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
title_sort	adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/385d5a0a20444620b152eb931564bc92
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Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.

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