Document Detail


Targeting urokinase and the transferrin receptor with novel, anti-mitotic N-alkylisatin cytotoxin conjugates causes selective cancer cell death and reduces tumor growth.
MedLine Citation:
PMID:  22111834     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic N-alkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20(th) and 1/10(th) of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.
Authors:
K L Vine; V Indira Chandran; J M Locke; L Matesic; J Lee; D Skropeta; J B Bremner; M Ranson
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Current cancer drug targets     Volume:  12     ISSN:  1873-5576     ISO Abbreviation:  Curr Cancer Drug Targets     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-16     Completed Date:  2012-09-20     Revised Date:  2014-09-25    
Medline Journal Info:
Nlm Unique ID:  101094211     Medline TA:  Curr Cancer Drug Targets     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  64-73     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimitotic Agents / administration & dosage*
Antineoplastic Agents / administration & dosage*,  metabolism
Cell Death / drug effects,  physiology
Cell Line, Tumor
Cell Survival / drug effects,  physiology
Cytotoxins / administration & dosage*
Drug Delivery Systems / methods*
Female
Humans
Isatin / administration & dosage*
Mice
Mice, Inbred BALB C
Mice, Nude
Receptors, Transferrin / antagonists & inhibitors*,  metabolism*
U937 Cells
Urokinase-Type Plasminogen Activator / antagonists & inhibitors*,  metabolism
Xenograft Model Antitumor Assays / methods
Chemical
Reg. No./Substance:
0/Antimitotic Agents; 0/Antineoplastic Agents; 0/Cytotoxins; 0/Receptors, Transferrin; 82X95S7M06/Isatin; EC 3.4.21.73/Urokinase-Type Plasminogen Activator

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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