Linked Life Data

9952321

Source:http://linkedlifedata.com/resource/pubmed/id/9952321

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1999-2-19
pubmed:abstractText
Folic acid (PteGlu)-enhanced intense synergy has been observed between nonpolyglutamylatable dihydrofolate reductase (DHFR) inhibitors and polyglutamylatable inhibitors of other folate-requiring enzymes, such as glycinamide ribonucleotide formyltransferase (GARFT) and thymidylate synthase. Since this phenomenon is potentially therapeutically useful, we explored its universality by examining the combined action of a DHFR inhibitor, trimetrexate (TMQ), with a GARFT inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]++ +thiazin-6-yl)-(S)-ethyl]-2,5-thienoylamino-L-glutamic acid (AG2034), in eight human cultured cell lines. Using a 96-well plate cell growth inhibition assay, four ileocecal adenocarcinoma cell lines [HCT-8, HCT-8/DW2 (Tomudex-resistant), HCT-8/DF2 (Tomudex-/FdUrd-resistant), and HCT-8/50 (adapted to 50 nM PteGlu)], three head and neck carcinoma cell lines [A253, FaDu, and Hep-2/500 (FdUrd-resistant)], and a non-small cell lung carcinoma cell line [H460] were treated for 96 hr with TMQ + AG2034 in the presence of 23 or 40 microM PteGlu. Cell growth was measured with the sulforhodamine B assay at the end of this period. Drug interactions were assessed by fitting a 7-parameter model including a synergism parameter, alpha, to data with weighted nonlinear regression. Isobologram analysis was also applied. At 23 microM PteGlu, cells exhibited similar intensities of Loewe synergy for the combination of TMQ + AG2034. Loewe synergy was abolished in HCT-8/50 cells cultured and studied in 50 nM PteGlu. At 40 microM PteGlu, the intensity of the combined action in all cell lines was increased However, the most intense Loewe synergy was seen with HCT-8, HCT-8/DF2, H460, FaDu, A253, and Hep-2/500 cells, whereas the HCT-8/50 subculture showed less of the phenomenon, and PteGlu enhancement was the least with HCT-8/DW2, a subline deficient in folylpolyglutamate synthetase (FPGS). The universality of the PteGlu-enhanced intense synergy phenomenon is suggested. Impaired FPGS activity and low-folate adaptation prior to treatment significantly lessen the degree of PteGlu enhancement.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
57
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
567-77
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:9952321-Adenocarcinoma, pubmed-meshheading:9952321-Antineoplastic Agents, pubmed-meshheading:9952321-Carcinoma, Squamous Cell, pubmed-meshheading:9952321-Cell Division, pubmed-meshheading:9952321-Colonic Neoplasms, pubmed-meshheading:9952321-Drug Resistance, Multiple, pubmed-meshheading:9952321-Drug Synergism, pubmed-meshheading:9952321-Folic Acid, pubmed-meshheading:9952321-Folic Acid Antagonists, pubmed-meshheading:9952321-Glutamates, pubmed-meshheading:9952321-Head and Neck Neoplasms, pubmed-meshheading:9952321-Humans, pubmed-meshheading:9952321-Hydroxymethyl and Formyl Transferases, pubmed-meshheading:9952321-Kinetics, pubmed-meshheading:9952321-Lung Neoplasms, pubmed-meshheading:9952321-Phosphoribosylglycinamide Formyltransferase, pubmed-meshheading:9952321-Pyrimidines, pubmed-meshheading:9952321-Trimetrexate, pubmed-meshheading:9952321-Tumor Cells, Cultured
pubmed:year
1999
pubmed:articleTitle
Folic acid-enhanced synergy for the combination of trimetrexate plus the glycinamide ribonucleotide formyltransferase inhibitor 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]thiazin -6-yl)-(S)-ethyl]-2,5-thienoylamino-L-glutamic acid (AG2034): comparison across sensitive and resistant human tumor cell lines.
pubmed:affiliation
Department of Biomathematics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't