Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity

doi:10.1158/1078-0432.CCR-09-0090

CNU IR > Pharmacy and Science > Dept. of Pharmacy > Periodical Articles > Item 310902800/23307

Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/23307

Title:	Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity
Authors:	Ting-Yi Juan Steve R. Roffler Hsien-San Hou Shih-Ming Huang Kai-Chuan Chen Yu-Lin Leu Zeljko M. Prijovich Cheng-Ping Yu Chang-Chieh Wu Guang-Huan Sun Tai-Lung Cha
Contributors:	藥學系
Date:	2009-07
Issue Date:	2010-12-29 15:05:16 (UTC+8)
Publisher:	Amer Assoc Cancer Research
Abstract:	Purpose: This study is aimed at investigating the in vivo antitumor activity of a novel cellimpermeable glucuronide prodrug, 9-aminocamptothecin glucuronide (9ACG), and elucidating the synergistically antitumor effects of antiangiogenesis therapy by targeting the tumor microenvironment. Experimental Design:We analyzed the antitumor effects of 9ACGalone or combinedwith antiangiogenicmonoclonal antibody DC101on human tumor xenografts by measuring tumor growth and mouse survival in BALB/c nu/nu nude and NOD/SCID mice. The drug delivery, immune response, and angiogenesis status in treated tumors were assessed by high performance liquid chromatography, immunohistochemistry, and immunofluorescence assays. Results:We developed a nontoxic and cell-impermeable glucuronide prodrug, 9ACG, which can only be activated by extracellular h-glucuronidase to become severely toxic. 9ACG possesses potent antitumor activity against human tumor xenografts in BALB/c nu/nu nude mice but not for tumors implanted in NOD/SCID mice deficient in macrophages and neutrophils, suggesting that these cells play an important role in activating 9ACG in the tumor microenvironment. Most importantly, antiangiogenic monoclonal antibody DC101potentiated single-dose 9ACG antitumor activity and prolonged survival of mice bearing resistant human colon tumor xenografts by providing strong h-glucuronidase activity and prodrug delivery through enhancing inflammatory cell infiltration and normalizing tumor vessels in the tumor microenvironment.We also show that inflammatory cells (neutrophils) were highly infiltrated in advanced human colon cancer tissues compared with normal counterparts. Conclusions: Our study provides in vivo evidence that 9ACG has potential for prodrug monotherapy or in combination with antiangiognesis treatment for tumors with infiltration of macrophage or neutrophil inflammatory cells.
Relation:	Clinical Cancer Research 15(14)：p.4600-4611
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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