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Breast Cancer Research

, 7:R1141

First Online: 16 November 2005Received: 31 May 2005Revised: 25 September 2005Accepted: 18 October 2005

Abstract

IntroductionIn view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses Ads is a major concern. Employing tissue specific promoters TSPs to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 EGP-2, cyclooxygenase-2 Cox-2, α-chemokine SDF-1 receptor stromal-cell-derived factor, CXCR4, secretory leukoprotease inhibitor SLPI and survivin.

MethodsWe employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver.

ResultsOverall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells.

ConclusionThese data suggest that the CXCR4 promoter has an ideal -breast cancer-on-liver-off- profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast.

AbbreviationsAdadenovirus

BSAbovine serum albumin

CARCoxsackie-Adenovirus-Receptor

CMVcytomegalovirus

Coxcyclooxygenase

CXCR4α-chemokine SDF-1 receptor

DAPI = 4-6-diamidino-2-phenylindole dihydrochloride

EGPepithelial glycoprotein

FCSfetal calf serum

GAPDHglyceraldehyde-3-phosphate dehydrogenase

MOImultiplicity of infection

PBSphosphate-buffered saline

PCRpolymerase chain reaction

SLPIsecretory leukoprotease inhibitor

TSPtissue specific promoter

UABUniversity of Alabama at Birmingham

UWUniversity of Wisconsin.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr1353 contains supplementary material, which is available to authorized users.

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Autor: Mariam A Stoff-Khalili - Alexander Stoff - Angel A Rivera - Nilam S Banerjee - Maaike Everts - Scott Young - Gene P Sie

Fuente: https://link.springer.com/







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