Linked Life Data

16424032

Source:http://linkedlifedata.com/resource/pubmed/id/16424032

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2006-1-20
pubmed:abstractText
The tumor microenvironment is notably enriched with a broad spectrum of proteases. The proteolytic specificities of peptide substrates provide modular chemical tools for the rational design of cell-impermeable prodrugs that are specifically activated by proteases extracellularly in the tumor microenvironment. Targeting cell-impermeable prodrug activation to tumor microenvironment will significantly reduce drug toxicity to normal tissues. The activated prodrug attacks both tumor and stroma cells through a "bystander effect" without selectively deleting target-producing cells, therefore further minimizing resistance and toxicity. Here, we showed that legumain, the only asparaginyl endopeptidase of the mammalian genome, is highly expressed by neoplastic, stromal, and endothelial cells in solid tumors. Legumain is present extracellularly in the tumor microenvironment, associated with matrix as well as cell surfaces and functional locally in the reduced pH of the tumor microenvironment. A novel legumain-activated, cell-impermeable doxorubicin prodrug LEG-3 was designed to be activated exclusively in the tumor microenvironment. Upon administration, there is a profound increase of the end-product doxorubicin in nuclei of cells in tumors but little in other tissues. This tumor microenvironment-activated prodrug completely arrested growth of a variety of neoplasms, including multidrug-resistant tumor in vivo and significantly extended survival without evidence of myelosuppression or cardiac toxicity. The tumor microenvironment-activated prodrug design can be extended to other proteases and chemotherapeutic compounds and provides new potentials for the rational development of more effective functionally targeted cancer therapeutics.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
66
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
970-80
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms.
pubmed:affiliation
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural