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Am J Cancer Res. 2017 Mar 1;7(3):657-672. eCollection 2017.

A tumor vessel-targeting fusion protein elicits a chemotherapeutic bystander effect in pancreatic ductal adenocarcinoma.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science CenterHouston, Texas 77030, USA.
3
Department of Imaging Physics, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science CenterHouston, Texas 77030, USA.
4
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical UniversityTaichung 404, Taiwan; Department of Biotechnology, Asia UniversityTaichung 413, Taiwan.
5
Department of Imaging Physics, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.
6
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science CenterHouston, Texas 77030, USA.
7
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.
8
Department of Cancer Biology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science CenterHouston, Texas 77030, USA.
9
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science CenterHouston, Texas 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical UniversityTaichung 404, Taiwan; Department of Biotechnology, Asia UniversityTaichung 413, Taiwan.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by a prominent desmoplastic stroma that may constrain tumor progression but also limit the access of therapeutic drugs. In this study, we explored a tumor-targeting strategy that enlists an engineered anti-angiogenic protein consisting of endostatin and cytosine deaminase linked to uracil phosphoribosyltransferase (EndoCD). This protein selectively binds to tumor vessels to compromise tumor angiogenesis and converts the non-toxic 5-fluorocytosine (5-FC) to the cytotoxic 5-fluorouracil to produce a chemotherapeutic bystander effect at the pancreatic tumor site. We found that resveratrol increased the protein stability of EndoCD through suppression of chymotrypsin-like proteinase activity and synergistically enhances EndoCD-mediated 5-FC-induced cell killing. In various PDAC mouse models, the EndoCD/5-FC/resveratrol regimen decreased intratumoral vascular density and stroma formation and enhances apoptosis in tumors cells as well as in surrounding endothelial, pancreatic stellate, and immune cells, leading to reduced tumor growth and extended survival. Thus, the EndoCD/5-FC/resveratrol combination may be an effective treatment option for PDAC.

KEYWORDS:

EndoCD; MRI; PDAC; resveratrol; two photon; ultrasound

PMID:
28401019
PMCID:
PMC5385650

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