Document Detail


The role of alpha-folate receptor-mediated transport in the antitumor activity of antifolate drugs.
MedLine Citation:
PMID:  14871988     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Raltitrexed, pemetrexed, lometrexol, and ZD9331 are antifolate drugs transported into cells via the ubiquitously expressed reduced-folate carrier. They display also high affinity for the alpha-folate receptor (alpha-FR), a low capacity folate transporter that is highly overexpressed in some epithelial tumors. The role of alpha-FR in the activity of the antifolates has been evaluated in two alpha-FR-overexpressing cell lines grown in a physiological concentration of folate (20 nM R,S-Leucovorin). EXPERIMENTAL DESIGN AND RESULTS: A431-FBP cells (transfected with the alpha-FR) were 3-5-fold more sensitive to the antifolates than A431 cells. KB cells (constitutive alpha-FR overexpression) were less sensitive to the drugs when coexposed to 1 microM folic acid to competitively inhibit binding to the alpha-FR. Raltitrexed, pemetrexed, and lometrexol are polyglutamated in cells leading to drug retention, e.g., the raltitrexed 4- and 24-h IC(50)s in A431 cells were approximately 0.6 and 0.008 microM, respectively, compared with 0.003 microM for 72-h continuous exposure. A431-FBP cells were approximately 3-fold more sensitive to raltitrexed and pemetrexed at all exposure times. ZD9331 is not polyglutamated, and the 4- and 24-h IC(50)s in A431 cells were >100 and approximately 100 microM, respectively, reducing to 2 and 0.1 microM, respectively, in A431-FBP cells. The ZD9331 4- and 24-h IC(50)s in KB cells were 20 and 1 microM, respectively, and reversible by coaddition of 1 microM folic acid. An in situ thymidylate synthase assay demonstrated continued thymidylate synthase inhibition after ZD9331-treated A431-FBP and KB, but not A431, cells were placed in drug-free medium for 16 h. A model is proposed in which the antifolates accumulate in the alpha-FR/endosomal apparatus, leading to slow release into the cytoplasm. In particular, this leads to cellular retention of the nonpolyglutamatable ZD9331. CONCLUSIONS: Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the alpha-FR.
Authors:
Davinder S Theti; Ann L Jackman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
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 Feb 
Date Detail:
Created Date:  2004-02-11     Completed Date:  2004-09-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1080-9     Citation Subset:  IM    
Affiliation:
Section of Medicine and the Cancer Research United Kingdom Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology
Antineoplastic Agents / pharmacology*
Biological Transport
Carrier Proteins / metabolism,  physiology*
Cell Line, Tumor
Cytosol / metabolism
Dose-Response Relationship, Drug
Folic Acid / metabolism
Folic Acid Antagonists / pharmacology*
Glutamates / pharmacology
Guanine / analogs & derivatives*,  pharmacology
Humans
Inhibitory Concentration 50
Models, Chemical
Neoplasms / metabolism
Quinazolines / pharmacokinetics,  pharmacology
Receptors, Cell Surface / metabolism,  physiology*
Thiophenes / pharmacology
Time Factors
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents; 0/Carrier Proteins; 0/Folic Acid Antagonists; 0/Glutamates; 0/Quinazolines; 0/Receptors, Cell Surface; 0/Thiophenes; 0/ZD 9331; 0/folate-binding protein; 112887-68-0/raltitrexed; 137281-23-3/pemetrexed; 59-30-3/Folic Acid; 73-40-5/Guanine

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


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