Document Detail


WP744 is a novel anthracycline with enhanced activity against neuroblastoma.
MedLine Citation:
PMID:  15501458     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Doxorubicin (Dox) is one of the most useful chemotherapeutic agents for patients with advanced neuroblastoma (NB). A series of Dox analogs with bulky substitutions at the C-4' at amino-sugar have been designed to impair interactions between the drug and P-glycoprotein (P-gp), a multidrug drug resistance (MDR) transporter. Two analogs, WP744 and WP769, were selected and their biological properties were compared with Dox and the daunorubicin-based bisintercalator WP631. These novel Dox analogs may have antitumor activity beyond MDR evasion. MATERIALS AND METHODS: MTT assays were used to determine the potency of three structurally altered Dox analogs against a panel of NB cell lines with and without amplification of the MYCN oncogene. Flow cytometry (FCM) was used to analyze apoptosis and cell death and phenotype cell lines for surface expression of the MDR protein P-gp. RESULTS: The 4'-O-benzylated Dox analogs WP744 and WP769 were 2 to 36 times more cytotoxic than Dox for the NB cell lines tested. The bis-intercalator WP631, despite its significantly greater affinity for DNA (>10,000-fold), was generally less potent against NB than Dox. In Tet21N cells, which conditionally express MYCN, greatly enhanced (nearly 6-fold) sensitivity to WP744 killing was seen when this oncogene was induced, while enhanced sensitivity to Dox was more modest (2-fold) under MYCN-induced conditions. Treatment with WP744 also resulted in enhanced apoptosis. Apoptosis, but not cell death, in response to either WP744 or Dox was inhibited by caspase inhibition, suggesting that cell death was not completely dependent upon apoptosis. P-gp expression was detectable on five NB cell lines. WP744 was more cytotoxic than Dox against both P-gp+ and P-gp- cells. CONCLUSIONS: These findings demonstrate that 4'-O-benzylation of the anthracycline molecule significantly enhances potency against NB independent of MYCN status, caspase activation, and MDR phenotype. However, WP744 demonstrated a unique synergy with MYCN for cell killing when this oncogene was specifically induced. WP744 may be more useful than conventional agents for the treatment of tumor clones that harbor defects in apoptotic pathways, in those with MYCN amplification, and in those with drug-resistant tumors.
Authors:
Thomas H Inge; Nathaniel L Harris; Jianqiang Wu; Richard G Azizkhan; Waldemar Priebe
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of surgical research     Volume:  121     ISSN:  0022-4804     ISO Abbreviation:  J. Surg. Res.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-10-25     Completed Date:  2004-11-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376340     Medline TA:  J Surg Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  187-96     Citation Subset:  IM    
Copyright Information:
Copyright 2004 Elsevier Inc.
Affiliation:
Children's Hospital Research Foundation, Department of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. thomas.inge@cchmc.org
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MeSH Terms
Descriptor/Qualifier:
Anthracyclines / pharmacology*
Apoptosis / drug effects
Cell Division / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Neuroblastoma / metabolism,  pathology*,  physiopathology*
Nuclear Proteins / metabolism
Oncogene Proteins / metabolism
P-Glycoprotein / metabolism
Chemical
Reg. No./Substance:
0/Anthracyclines; 0/MYCN protein, human; 0/Nuclear Proteins; 0/Oncogene Proteins; 0/P-Glycoprotein; 0/WP 744

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