Abstract:
:Targeted thrombotic eradication of solid tumors is a novel therapeutic strategy. The feasibility, efficacy, selectivity, and safety are dependent on multiple variables of protein design, molecular assembly, vascular target, and exclusive restriction of function to the tumor vasculature. To advance this strategy, we describe a design of an integrin targeting selective tumor vascular thrombogen. We adopted the fibronectin structural motif of tandem repeating modules with four type III repeat modules of fibronectin followed by two structurally homologous modules of the extracellular domain of tissue factor. This hybrid protein of six tandem modules recognizes integrins and selectively docks and initiates the thrombogenic protease cascade locally on the target cell surfaces. The protein is inactive in blood but is functionally active once assembled on integrin-positive cells. When administered i.v. to tumor-bearing mice, it selectively induces extensive local microthrombosis of the tumor microvasculature. The principles are addressed from the perspective of protein structural design for a class of selective tumor vascular thrombogen proteins that, through interaction with tumor angiogenic endothelium, elicit thrombotic occlusion rather than apoptosis or arrest of angiogenesis. This response can produce local tumor infarction followed by intratumoral ischemia-reperfusion injury, inflammation, and a local host tumor eradicative response.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Liu C,Dickinson C,Shobe J,Doñate F,Ruf W,Edgington Tkeywords:
subject
Has Abstractpub_date
2004-07-01 00:00:00pages
793-801issue
7eissn
1535-7163issn
1538-8514pii
3/7/793journal_volume
3pub_type
杂志文章abstract::STAT3 is an important transcriptional factor for cell growth, differentiation, and apoptosis. Although evidence suggests a positive role for STAT3 in cancer, the inhibitory effects of tumor STAT3 on natural killer (NK) cell functions in human hepatocellular carcinoma are unclear. In this study, we found that blocking ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1087
更新日期:2013-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0211
更新日期:2016-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0052
更新日期:2016-04-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-03-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0798
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0302
更新日期:2018-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0079
更新日期:2007-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-02-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0937
更新日期:2009-03-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0916
更新日期:2018-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0040
更新日期:2005-07-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0182
更新日期:2011-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0132
更新日期:2007-08-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0387
更新日期:2020-01-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0934
更新日期:2009-04-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0450
更新日期:2008-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0028
更新日期:2016-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0378
更新日期:2020-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2005-02-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2004-03-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0942
更新日期:2012-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:10.1158/1535-7163.MCT-10-0263
更新日期:2010-08-01 00:00:00
abstract::Hepatocellular carcinoma is highly chemoresistant, and ATP-binding cassette subfamily G member 2 (ABCG2) is thought to play a critical role in this drug resistance. The present study aims to develop effective therapeutic strategies to decrease ABCG2 expression level and to surmount drug resistance in hepatocellular ca...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0201
更新日期:2013-12-01 00:00:00
abstract::Gene therapy is a promising approach for the treatment of cancers. Strategies for gene vector delivery include systemic and local-regional approaches. Intratumoral delivery of vectors has generally employed direct injections into single or multiple locations throughout the tumor volume. However, this approach leads to...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2004-06-01 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistanc...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0253
更新日期:2016-11-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0535
更新日期:2012-08-01 00:00:00
abstract::To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0276
更新日期:2020-08-26 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2004-12-01 00:00:00
abstract::Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., (V600E)B-Raf A375, IC(50) on cells = 2 nmol/L; ED(50) on...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0181
更新日期:2010-08-01 00:00:00