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Title: Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer

Abstract

Background: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. Results: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our 'gene therapy' approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce {approx} 50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by {approx} 35% tumor progression in vivomore » in already established tumors. Conclusions: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.« less

Authors:
 [1];  [2];  [1];  [1];  [2];  [3];  [2]; ; ;  [1];  [2];  [1];  [2];  [2]
  1. Integrated Cancer Prevention Center, Tel Aviv (Israel)
  2. (Israel)
  3. Lung and Allergy Institute, Tel Aviv Sourasky Medical Center, Tel Aviv (Israel)
Publication Date:
OSTI Identifier:
22212292
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 318; Journal Issue: 2; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENOVIRUS; APOPTOSIS; CARCINOGENESIS; GENE THERAPY; IN VITRO; IN VIVO; LETHAL GENES; METASTASES; MICE; MUTATIONS; NEOPLASMS; ONCOGENES; PROMOTERS

Citation Formats

Naumov, Inna, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Kazanov, Dina, Lisiansky, Victoria, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Starr, Alex, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Aroch, Ilan, Shapira, Shiran, Kraus, Sarah, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Arber, Nadir, E-mail: narber@post.tau.ac.il, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv. Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer. United States: N. p., 2012. Web. doi:10.1016/J.YEXCR.2011.09.015.
Naumov, Inna, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Kazanov, Dina, Lisiansky, Victoria, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Starr, Alex, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Aroch, Ilan, Shapira, Shiran, Kraus, Sarah, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Arber, Nadir, E-mail: narber@post.tau.ac.il, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv. Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer. United States. doi:10.1016/J.YEXCR.2011.09.015.
Naumov, Inna, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Kazanov, Dina, Lisiansky, Victoria, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Starr, Alex, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Aroch, Ilan, Shapira, Shiran, Kraus, Sarah, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Arber, Nadir, E-mail: narber@post.tau.ac.il, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv. Sun . "Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer". United States. doi:10.1016/J.YEXCR.2011.09.015.
@article{osti_22212292,
title = {Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer},
author = {Naumov, Inna and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Kazanov, Dina and Lisiansky, Victoria and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Starr, Alex and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Aroch, Ilan and Shapira, Shiran and Kraus, Sarah and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Arber, Nadir, E-mail: narber@post.tau.ac.il and Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv},
abstractNote = {Background: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. Results: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our 'gene therapy' approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce {approx} 50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by {approx} 35% tumor progression in vivo in already established tumors. Conclusions: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.},
doi = {10.1016/J.YEXCR.2011.09.015},
journal = {Experimental Cell Research},
number = 2,
volume = 318,
place = {United States},
year = {Sun Jan 15 00:00:00 EST 2012},
month = {Sun Jan 15 00:00:00 EST 2012}
}