Document Detail


Lack of impact of the loss of constitutive folate receptor alpha expression, achieved by RNA Interference, on the activity of the new generation antifolate pemetrexed in HeLa cells.
MedLine Citation:
PMID:  15585634     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pemetrexed [PMX (Alimta)] is a new generation antifolate with activity in a variety of solid tumors. It is an excellent substrate for most folate transporters, notably the reduced folate carrier (RFC) and folate receptor (FR)-alpha. The role of FR-alpha in PMX pharmacological activity is uncertain. Whereas high-level expression may enhance the activity of this agent, it is not clear what role constitutive levels of this transporter contribute to PMX activity. In this study, constitutive levels of FR-alpha expression were abolished by small interfering RNA-induced silencing in HeLa cells and RFC-null HeLa R5 cells as confirmed by Northern blotting, immunohistochemistry, and cell surface binding. PMX growth inhibition was unchanged in HeLa and R5 cells in the absence of FR-alpha expression. Loss of FR-alpha expression did not decrease net accumulation of PMX in either wild-type or RFC-null HeLa cells. Likewise, folate pools in wild-type HeLa cells were not decreased by FR-alpha gene silencing and were negligibly affected in the RFC-null R5 subline grown with 5-formyltetrahydrofolate. FR-alpha surface binding in HeLa cells was shown to be greater than that in a variety of other human solid tumor cell lines. Hence, constitutively expressed FR-alpha in HeLa cells does not contribute to PMX activity in the presence or absence of RFC function. This is likely the case in many human solid tumor cell lines.
Authors:
Shrikanta Chattopadhyay; Yanhua Wang; Rongbao Zhao; I David Goldman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  10     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-12-08     Completed Date:  2005-04-14     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7986-93     Citation Subset:  IM    
Affiliation:
Department of Medicine, Albert Einstein College of Medicine and Albert Einstein Cancer Research Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Base Sequence
Blotting, Northern
Carrier Proteins / genetics*
Fluorescent Antibody Technique
Folic Acid / metabolism*
Folic Acid Antagonists / metabolism,  pharmacology*
Formyltetrahydrofolates
Glutamates / metabolism,  pharmacology*
Guanine / analogs & derivatives*,  metabolism,  pharmacology*
Hela Cells
Humans
Molecular Sequence Data
Neoplasms / enzymology*,  genetics
RNA Interference*
Receptors, Cell Surface / deficiency,  genetics*
Thymidylate Synthase / antagonists & inhibitors
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA-82621/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Folic Acid Antagonists; 0/Formyltetrahydrofolates; 0/Glutamates; 0/Receptors, Cell Surface; 0/folate-binding protein; 137281-23-3/pemetrexed; 59-30-3/Folic Acid; 73-40-5/Guanine; EC 2.1.1.45/Thymidylate Synthase

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


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