| Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase. | |
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MedLine Citation:
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PMID: 1596289 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The thymidylate synthase (TS) inhibitor ICI D1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N -methylamino]-2 - thenoyl)-S-glutamic acid) is a structural analogue of the substrate N5,N10-methylenetetrahydrofolate (5,10-CH2FH4) and is currently under clinical evaluation as a treatment for cancer. The compound is shown here to be a mixed non-competitive inhibitor of TS from murine leukemia (L1210) cells when 5,10-CH2FH4 is varied. This result suggests formation of an inactive complex between TS, 5,10-CH2FH4 and the inhibitor. Thus, binding to only one of the two active sites on the TS homodimer may be sufficient to prevent catalysis fully. Treatment of L1210 cells with ICI D1694 is known to cause intracellular accumulation of the tetraglutamate derivative which is shown here to have a 60-fold higher affinity for TS. The IC50 for inhibition of L1210 cell growth is below the Ki value of ICI D1694 for L1210 TS but above that of the tetraglutamate. The formation of polyglutamates and concentration of drug inside cells, therefore, seem to be responsible for biological activity. |
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Authors:
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W H Ward; R Kimbell; A L Jackman |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biochemical pharmacology Volume: 43 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 1992 May |
Date Detail:
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Created Date: 1992-06-26 Completed Date: 1992-06-26 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 2029-31 Citation Subset: IM |
Affiliation:
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ICI Pharmaceuticals Mereside, Macclesfield Cheshire, U.K. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Binding Sites Cell Division / drug effects Kinetics Leukemia L1210 / enzymology* Mice Quinazolines / pharmacology* Tetrahydrofolates / metabolism Thiophenes / pharmacology* Thymidylate Synthase / antagonists & inhibitors*, isolation & purification Tumor Cells, Cultured / enzymology |
| Chemical | |
Reg. No./Substance:
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0/Quinazolines; 0/Tetrahydrofolates; 0/Thiophenes; 112887-68-0/raltitrexed; 3432-99-3/5,10-methylenetetrahydrofolate; EC 2.1.1.45/Thymidylate Synthase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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