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Activity of the thymidylate synthase inhibitor 2-desamino-N10-propargyl-5,8-dideazafolic acid and related compounds in murine (L1210) and human (W1L2) systems in vitro and in L1210 in vivo.
TLDR
2-Desamino-5,8-dideazafolate retains quite good activity against both the TS-overproducing W1L2:C1 line and the L1210 cell line grown in the presence of thymidine, suggesting that a secondary locus of action may be involved. Expand
Thymidylate synthase inhibitors: the in vitro activity of a series of heterocyclic benzoyl ring modified 2-desamino-2-methyl-N10-substituted-5,8-dideazafolates.
TLDR
ICI D1694 may elicit toxicities in man more typical of an antimetabolite than of CB3717, and the clinical evaluation of ICI D 1694 may further the understanding of the role that metabolism to polyglutamates may have in therapeutic activity. Expand
Secretion of gamma-glutamyl hydrolase in vitro.
TLDR
Altering in the cellular and secreted H35 cell gamma-glutamyl hydrolase levels in response to changes in culture conditions revealed that glutamine enhances activity while insulin diminishes it, which suggests that both act primarily as endopeptidases. Expand
Quinazoline antifolate thymidylate synthase inhibitors: heterocyclic benzoyl ring modifications.
TLDR
The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folylpolyglutamate synthetase. Expand
Secretion of γ-Glutamyl Hydrolase in Vitro
TLDR
Alterations in the cellular and secreted H35 cell γ-glutamyl hydrolase levels in response to changes in culture conditions revealed that glutamine enhances activity while insulin diminishes it, suggesting that both act primarily as endopeptidases. Expand
Intracellular Location of Thymidylate Synthase and Its State of Phosphorylation*
TLDR
Findings suggest that this enzyme’s contribution to the cell cycle may be more complex than believed previously, and that the enzyme appears to be a phosphoprotein, similar to that found for other proteins associated with cell division and signal transduction. Expand
Identification of the major phosphorylation domain of murine mdr1b P-glycoprotein. Analysis of the protein kinase A and protein kinase C phosphorylation sites.
TLDR
Domain mapping, utilizing a combination of cyanogen bromide digestion and immunoblot analysis, was used to reveal the major phosphorylation sites in murine mdr1b P-glycoprotein, and the linker region, although shorter than the R domain, fits the operational definition of the Rdomain of cystic fibrosis conductance regulator. Expand
Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C2 position.
TLDR
The potential of such compounds as useful antitumor agents was further enhanced by the finding that the improved aqueous solubilities of compounds such as 3a over 1a were reflected in vivo in that 3a was at least 5 times less toxic to mice than 1a. Expand
Biochemical and biological studies on 2-desamino-2-methylaminopterin, an antifolate the polyglutamates of which are more potent than the monoglutamate against three key enzymes of folate metabolism.
TLDR
Findings support the hypothesis that dmAMT requires intracellular polyglutamylation for activity and indicate that replacement of the 2-amino group by 2-methyl is as acceptable a structural modification in antifolates targeted against DHFR as it is in ants targeted against TS. Expand
Human lymphoblastoid cells with acquired resistance to C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid: a novel folate-based thymidylate synthase inhibitor.
TLDR
The characterization of human lymphoblastoid cell lines with acquired resistance to a novel folate-based thymidylate synthase (TS) appears unlikely that resistance is due to an altered TS enzyme having a lower affinity for ICI198583, and may have important implications in light of the rapid onset of resistance to antifolates in the clinic. Expand
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