Document Detail

Development of methotrexate proline prodrug to overcome resistance by MDA-MB-231 cells.
MedLine Citation:
PMID:  20674353     Owner:  NLM     Status:  MEDLINE    
The resistance to methotrexate by a number of cancer cells such as breast cancer cell-line MDA-MB-231 due to poor permeability renders it less effective as an anticancer agent for these cells. Proline prodrug of methotrexate (Pro-MTX) was designed as a substrate of prolidase which is specific for imido bond of dipeptide containing proline and expected to penetrate MDA-MB-231 cells more efficiently. The prodrug was synthesized by solid-phase peptide synthesis method and examined as a substrate of pure prolidase as well as cell homogenate. The cytotoxicity against MDA-MB-231 and non-methotrexate resistant breast cancer cell line, MCF-7 was also examined by XTT assay. The results showed that Pro-MTX was a substrate of prolidase. It was also shown that the prodrug could be converted to parent drug methotrexate in Caco-2 and HeLa cell homogenate. When tested with Caco-2 and MCF-7 cells, Pro-MTX showed weaker cytotoxicity compared with methotrexate. But for methotrexate resistant MDA-MB-231 cells, Pro-MTX showed stronger activity than methotrexate. The results indicated that the proline prodrug of methotrexate may overcome the resistance of human breast cancer cells in culture.
Zhiqian Wu; Anandkumar Shah; Namrata Patel; Xudong Yuan
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Publication Detail:
Type:  Journal Article     Date:  2010-07-11
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  20     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-16     Completed Date:  2010-12-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  5108-12     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Ltd. All rights reserved.
Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA.
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MeSH Terms
Antimetabolites, Antineoplastic / pharmacology*
Breast Neoplasms / pathology*
Cell Line, Tumor
Drug Resistance, Neoplasm*
Methotrexate / pharmacology*
Prodrugs / pharmacology*
Proline / chemistry*
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Prodrugs; 147-85-3/Proline; 59-05-2/Methotrexate

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

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