A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models

Autores
Cafferata, Eduardo Gustavo Alfredo; Macció, Daniela Rita; Lopez, Maria Veronica; Viale, Diego Luis; Carbone, Cecilia; Mazzolini Rizzo, Guillermo Daniel; Podhajcer, Osvaldo Luis
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
PURPOSE: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo. RESULTS: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs. CONCLUSIONS: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC
Fil: Cafferata, Eduardo Gustavo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Macció, Daniela Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Lopez, Maria Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Viale, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Carbone, Cecilia. Universidad Nacional de la Plata. Facultad de Ciencias Veterinarias. Departamento de Microbiología. Cátedra de Animales de Laboratorio; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Materia
Colorectal Cancer
Gene Therapy
Conditionally Replicative Adenovirus
A33 Promoter
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/28296
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/28296
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer modelsCafferata, Eduardo Gustavo AlfredoMacció, Daniela RitaLopez, Maria VeronicaViale, Diego LuisCarbone, CeciliaMazzolini Rizzo, Guillermo DanielPodhajcer, Osvaldo LuisColorectal CancerGene TherapyConditionally Replicative AdenovirusA33 Promoterhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3PURPOSE: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo. RESULTS: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs. CONCLUSIONS: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRCFil: Cafferata, Eduardo Gustavo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Macció, Daniela Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Lopez, Maria Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Viale, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Carbone, Cecilia. Universidad Nacional de la Plata. Facultad de Ciencias Veterinarias. Departamento de Microbiología. Cátedra de Animales de Laboratorio; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaAmerican Association for Cancer Research2009-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/28296Cafferata, Eduardo Gustavo Alfredo; Macció, Daniela Rita; Lopez, Maria Veronica; Viale, Diego Luis; Carbone, Cecilia; et al.; A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models; American Association for Cancer Research; Clinical Cancer Research; 15; 9; 3-2009; 3037-30491078-04321078-0432CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/15/9/3037info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-08-1161info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:53:26Zoai:ri.conicet.gov.ar:11336/28296instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:53:26.997CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
title A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
spellingShingle A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
Cafferata, Eduardo Gustavo Alfredo
Colorectal Cancer
Gene Therapy
Conditionally Replicative Adenovirus
A33 Promoter
title_short A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
title_full A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
title_fullStr A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
title_full_unstemmed A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
title_sort A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models
dc.creator.none.fl_str_mv Cafferata, Eduardo Gustavo Alfredo
Macció, Daniela Rita
Lopez, Maria Veronica
Viale, Diego Luis
Carbone, Cecilia
Mazzolini Rizzo, Guillermo Daniel
Podhajcer, Osvaldo Luis
author Cafferata, Eduardo Gustavo Alfredo
author_facet Cafferata, Eduardo Gustavo Alfredo
Macció, Daniela Rita
Lopez, Maria Veronica
Viale, Diego Luis
Carbone, Cecilia
Mazzolini Rizzo, Guillermo Daniel
Podhajcer, Osvaldo Luis
author_role author
author2 Macció, Daniela Rita
Lopez, Maria Veronica
Viale, Diego Luis
Carbone, Cecilia
Mazzolini Rizzo, Guillermo Daniel
Podhajcer, Osvaldo Luis
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Colorectal Cancer
Gene Therapy
Conditionally Replicative Adenovirus
A33 Promoter
topic Colorectal Cancer
Gene Therapy
Conditionally Replicative Adenovirus
A33 Promoter
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv PURPOSE: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo. RESULTS: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs. CONCLUSIONS: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC
Fil: Cafferata, Eduardo Gustavo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Macció, Daniela Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Lopez, Maria Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Viale, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Carbone, Cecilia. Universidad Nacional de la Plata. Facultad de Ciencias Veterinarias. Departamento de Microbiología. Cátedra de Animales de Laboratorio; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
description PURPOSE: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo. RESULTS: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs. CONCLUSIONS: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC
publishDate 2009
dc.date.none.fl_str_mv 2009-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/28296
Cafferata, Eduardo Gustavo Alfredo; Macció, Daniela Rita; Lopez, Maria Veronica; Viale, Diego Luis; Carbone, Cecilia; et al.; A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models; American Association for Cancer Research; Clinical Cancer Research; 15; 9; 3-2009; 3037-3049
1078-0432
1078-0432
CONICET Digital
CONICET
url http://hdl.handle.net/11336/28296
identifier_str_mv Cafferata, Eduardo Gustavo Alfredo; Macció, Daniela Rita; Lopez, Maria Veronica; Viale, Diego Luis; Carbone, Cecilia; et al.; A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models; American Association for Cancer Research; Clinical Cancer Research; 15; 9; 3-2009; 3037-3049
1078-0432
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/15/9/3037
info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-08-1161
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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