Linked Life Data

7495479

Source:http://linkedlifedata.com/resource/pubmed/id/7495479

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
1996-1-16
pubmed:abstractText
Many quinazoline thymidylate synthase (TS) inhibitors undergo intracellular metabolism to polyglutamate forms which can significantly alter their activity and pharmacodynamics through improved TS inhibition and drug retention. When a series of quinazolines was tested for inhibitory activity towards TS (IC50 0.001-2 microM) and the growth of L1210 cells (IC50 0.005-10 microM), no direct correlation was observed. However, a very good correlation was apparent if a L1210 variant cell line (L1210: RD1694) was used. This line is deficient in its ability to form antifolate polyglutamates. A number of other intact cell methods have also been developed which estimate the contribution that intracellular polyglutamation makes to a compound's activity. These assays were validated using a series of quinazoline-based TS inhibitors with well-defined activity for TS, folypolyglutamate synthetase (FPGS) and the reduced-folate cell membrane carrier (RFC). Short-exposure growth-inhibition assays or the measurement of TS activity in situ after various incubation times, followed by different lengths of time in drug-free medium, can indicate both the speed and extent of appearance of retentive forms (usually polyglutamates). Continuous-exposure growth-inhibition assays, in the presence of leucovorin (LV), are also useful, since only the growth-inhibitory potency of polyglutamated analogues is significantly decreased by LV. Highly polyglutamated compounds, e.g. ZD1694, are virtually inactive in the presence of a high concentration of LV. It is proposed that these methods, when considered together, provide a greater degree of information concerning the rate and extent of polyglutamation of a particular compound than isolated FPGS assays alone.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/CB 3717, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Folic Acid, http://linkedlifedata.com/resource/pubmed/chemical/Folic Acid Antagonists, http://linkedlifedata.com/resource/pubmed/chemical/Leucovorin, http://linkedlifedata.com/resource/pubmed/chemical/Methotrexate, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Synthases, http://linkedlifedata.com/resource/pubmed/chemical/Polyglutamic Acid, http://linkedlifedata.com/resource/pubmed/chemical/Pteroylpolyglutamic Acids, http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines, http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase, http://linkedlifedata.com/resource/pubmed/chemical/folylpolyglutamate synthetase
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0266-9536
pubmed:author
pubmed:issnType
Print
pubmed:volume
10
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
555-72
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Quinazoline thymidylate synthase inhibitors: methods for assessing the contribution of polyglutamation to their in vitro activity.
pubmed:affiliation
CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Sutton, Surrey, UK.
pubmed:publicationType
Journal Article