Document Detail


Studies on the mechanism of action of dextrin-phospholipase A2 and its suitability for use in combination therapy.
MedLine Citation:
PMID:  20163158     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The bioresponsive conjugate dextrin-phospholipase A2 (PLA2) is a novel anticancer polymer therapeutic. Dextrin conjugation decreases PLA2 bioactivity, but this can be restored following triggered degradation by alpha-amylase. The conjugate displays reduced hemolytic activity but retains, or shows enhanced, cytotoxicity in vitro that partially correlates with epidermal growth factor receptor (EGFR) expression. Here, we investigate further the mechanism of action of dextrin-PLA2 with the aim of judging its potential for combination with tyrosine kinase inhibitors (TKI) and/or chemotherapy and selecting the first models for in vivo evaluation. The endocytic fate of Oregon Green (OG)-labeled probes was assessed in MCF-7 cells. Whereas PLA2-OG showed greatest membrane binding, the dextrin-PLA2-OG conjugate displayed higher internalization. Moreover, cells incubated with PLA(2)-OG and dextrin-PLA2-OG showed an altered pattern of intracellular vesicle distribution compared to dextrin-OG. When cell lines known to express different levels of EGFR were used to assess cytotoxicity, free PLA2 activity was enhanced by addition of EGF whereas the conjugate was less cytotoxic, perhaps due to differences in their PK/PD profile. Co-incubation of cells with the TKI inhibitor, gefitinib, led to reduced cytotoxicity of both PLA2 and dextrin-PLA2 suggesting a TK-mediated PLA2 mechanism of action. However, the enhanced cytotoxicity seen in the presence of doxorubicin suggested potential for development of a dextrin-PLA2/doxorubicin combination therapy.
Authors:
Elaine L Ferguson; Simon C W Richardson; Ruth Duncan
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  7     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-05     Completed Date:  2010-06-29     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  510-21     Citation Subset:  IM    
Affiliation:
Centre for Polymer Therapeutics, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3XF, UK. FergusonEL@cf.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry,  therapeutic use*
Cell Line, Tumor
Dextrins / chemistry*
Drug Therapy, Combination / methods*
Flow Cytometry
HT29 Cells
Humans
Microscopy, Confocal
Models, Biological
Molecular Structure
Phospholipases A2 / chemistry*,  therapeutic use*
Protein Kinase Inhibitors / therapeutic use
Quinazolines / therapeutic use
Receptor, Epidermal Growth Factor / metabolism
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Dextrins; 0/Protein Kinase Inhibitors; 0/Quinazolines; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.1.1.4/Phospholipases A2; S65743JHBS/gefitinib

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