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

作者：Chen Chun Te; Chen Yi Chun; Du Yi; Han Zhenbo; Ying Haoqiang; Bouchard Richard R; Hsu Jennifer L; Hsu Jung Mao; Mitcham Trevor M; Chen Mei Kuang; Sun Hui Lung; Chang Shih Shin; Li Donghui; Chang Ping; DePinho Ronald A; Hung Mien Chie^*

来源：American Journal of Cancer Research, 2017, 7(3): 657-+.

• PDAC
• EndoCD
• resveratrol
• two photon
• MRI
• ultrasound

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.

• 出版日期2017
• 单位中国医科大学