PMID- 20674353
OWN - NLM
STAT- MEDLINE
DCOM- 20101206
LR  - 20131121
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 20
IP  - 17
DP  - 2010 Sep 1
TI  - Development of methotrexate proline prodrug to overcome resistance by MDA-MB-231 
      cells.
PG  - 5108-12
LID - 10.1016/j.bmcl.2010.07.024 [doi]
AB  - 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.
CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
FAU - Wu, Zhiqian
AU  - Wu Z
AD  - Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy 
      and Health Sciences, Long Island University, Brooklyn, NY 11201, USA. 
      james.wu@liu.edu
FAU - Shah, Anandkumar
AU  - Shah A
FAU - Patel, Namrata
AU  - Patel N
FAU - Yuan, Xudong
AU  - Yuan X
LA  - eng
PT  - Journal Article
DEP - 20100711
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Prodrugs)
RN  - 9DLQ4CIU6V (Proline)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Breast Neoplasms/*pathology
MH  - Cell Line, Tumor
MH  - *Drug Resistance, Neoplasm
MH  - Humans
MH  - Methotrexate/*pharmacology
MH  - Prodrugs/*pharmacology
MH  - Proline/*chemistry
EDAT- 2010/08/03 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/08/03 06:00
PHST- 2010/06/07 00:00 [received]
PHST- 2010/07/06 00:00 [revised]
PHST- 2010/07/07 00:00 [accepted]
PHST- 2010/08/03 06:00 [entrez]
PHST- 2010/08/03 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - S0960-894X(10)00980-7 [pii]
AID - 10.1016/j.bmcl.2010.07.024 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2010 Sep 1;20(17):5108-12. doi: 10.1016/j.bmcl.2010.07.024. 
      Epub 2010 Jul 11.