Linked Life Data

12049481

Source:http://linkedlifedata.com/resource/pubmed/id/12049481

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4-5
pubmed:dateCreated
2002-6-6
pubmed:abstractText
Limitations of low mol. wt anticancer drugs are short tumor exposure times and toxicity to normal tissue. Methotrexate (MTX) covalently linked to human serum albumin (HSA) as a macromolecular carrier caused tumor regressions concomitant with a favorable toxicity profile in a clinical phase I trial (Hartung et aL, Clin. Cancer Res., 1999, 5, 753). We examined the uptake, intracellular degradation, metabolism and thymidylate synthase (TS) inhibition of MTX-HSA in the T-cell leukemia line CCRF-CEM and the MTX transport resistant clone CCRF-CEM/MTX. The number of MTX molecules per albumin molecule was determined by electrospray mass spectrometry. A loading ratio (LR) of approximately 1.4 mol MTX/albumin revealed intact complexes with one and two MTX molecules/albumin. In the complex with an LR of 5.7, albumin with up to 16 MTX molecules was seen. MTX-HSA was taken up by CCRF-CEM cells via endocytosis and cleaved by lysosomal enzymes. Liberated MTX was a poor substrate of folylpolyglutamate synthetase and was exported into the medium. TS was inhibited and cell survival was impaired by MTX-HSA in a time- and concentration-dependent manner. CCRF-CEM/MTX cells exhibited a growth inhibition of 30-40% after MTX-HSA treatment, but no TS inhibition. The alternative uptake route via endocytosis enables MTX-HSA to overcome transport resistance to MTX.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0266-9536
pubmed:author
pubmed:issnType
Print
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
227-37
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12049481-Antimetabolites, Antineoplastic, pubmed-meshheading:12049481-Carrier Proteins, pubmed-meshheading:12049481-Clone Cells, pubmed-meshheading:12049481-Drug Resistance, Neoplasm, pubmed-meshheading:12049481-Humans, pubmed-meshheading:12049481-Immunochemistry, pubmed-meshheading:12049481-Leukemia, T-Cell, pubmed-meshheading:12049481-Lysosomes, pubmed-meshheading:12049481-Methotrexate, pubmed-meshheading:12049481-Molecular Weight, pubmed-meshheading:12049481-Polyglutamic Acid, pubmed-meshheading:12049481-Protein Binding, pubmed-meshheading:12049481-Serum Albumin, pubmed-meshheading:12049481-Spectrometry, Mass, Electrospray Ionization, pubmed-meshheading:12049481-Survival Analysis, pubmed-meshheading:12049481-Thymidylate Synthase, pubmed-meshheading:12049481-Tumor Cells, Cultured
pubmed:articleTitle
Mode of action of methotrexate-albumin in a human T-cell leukemia line and activity against an MTX-resistant clone.
pubmed:affiliation
Division of Molecular Toxicology, German Cancer Research Center, Heidelberg.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't