Biomaterial Database

Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells. 1994

B Mitrovski, and J Pressacco, and S Mandelbaum, and C Erlichman

Division of Experimental Therapeutics, Ontario Cancer Institute, Toronto, Canada.

The TS-inhibitory effects induced by a 24-h exposure to the folate-based TS inhibitors CB3717, C2-desamino analogs of CB3717 including D1694, and BW1843U89 were quantitated using the MGH-U1 human bladder carcinoma. The effects of D1694 on the time course of TS inhibition and on intracellular deoxyuridine monophosphate (dUMP) accumulation and deoxyuridine (dUrd) production were evaluated. D1694 and BW1843U89 were the most active TS inhibitors with IC50 values of 2.4 and 0.5 nM, respectively. The C2-desamino C2-methyl dideazafolates were 27-292 times more potent than the parent CB3717 as TS inhibitors. A methyl group at the C2 position of CB3717 had the most dramatic effect, whereas a thiazole substitution for a benzyl added a small benefit and N10 substitution had a limited impact on TS-inhibitory potency and clonogenic survival. There was a significant correlation between the IC50 values for TS inhibition and those for cytotoxic potency obtained for these drugs. LV and thymidine protected cells from these folate-based TS inhibitors. Intracellular dUMP levels following 24 h D1694 (IC50) exposure increased 7-fold. Levels of dUrd effluxing into the media increased up to 4.5 microM following a 24-h exposure to D1694 (IC90). We conclude that (a) C2-desamino C2-methyl dideazafolates are potent TS inhibitors, (b) TS inhibition requires prolonged exposure with these folate TS inhibitors, (c) survival is correlated with inhibition of TS for the folate-based TS inhibitors and (d) the biochemical consequences of TS inhibition include increased dUMP and dUrd levels.

UI	MeSH Term	Description	Entries
D007211	Indoles	Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D011799	Quinazolines	A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring.	Quinazoline
D001749	Urinary Bladder Neoplasms	Tumors or cancer of the URINARY BLADDER.	Bladder Cancer,Bladder Neoplasms,Cancer of Bladder,Bladder Tumors,Cancer of the Bladder,Malignant Tumor of Urinary Bladder,Neoplasms, Bladder,Urinary Bladder Cancer,Bladder Cancers,Bladder Neoplasm,Bladder Tumor,Cancer, Bladder,Cancer, Urinary Bladder,Neoplasm, Bladder,Neoplasm, Urinary Bladder,Tumor, Bladder,Tumors, Bladder,Urinary Bladder Neoplasm
D002470	Cell Survival	The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.	Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D003856	Deoxyuracil Nucleotides	Uracil nucleotides which contain deoxyribose as the sugar moiety.	Deoxyuridine Phosphates,Nucleotides, Deoxyuracil,Phosphates, Deoxyuridine
D003857	Deoxyuridine	2'-Deoxyuridine. An antimetabolite that is converted to deoxyuridine triphosphate during DNA synthesis. Laboratory suppression of deoxyuridine is used to diagnose megaloblastic anemias due to vitamin B12 and folate deficiencies.	(beta 1-(2-Deoxyribopyranosyl))thymidine
D005492	Folic Acid	A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses (POACEAE). Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia.	Pteroylglutamic Acid,Vitamin M,Folacin,Folate,Folic Acid, (D)-Isomer,Folic Acid, (DL)-Isomer,Folic Acid, Calcium Salt (1:1),Folic Acid, Monopotassium Salt,Folic Acid, Monosodium Salt,Folic Acid, Potassium Salt,Folic Acid, Sodium Salt,Folvite,Vitamin B9,B9, Vitamin
D005493	Folic Acid Antagonists	Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033)	Antifolate,Antifolates,Dihydrofolate Reductase Inhibitor,Folic Acid Antagonist,Dihydrofolate Reductase Inhibitors,Folic Acid Metabolism Inhibitors,Acid Antagonist, Folic,Acid Antagonists, Folic,Antagonist, Folic Acid,Antagonists, Folic Acid,Inhibitor, Dihydrofolate Reductase,Inhibitors, Dihydrofolate Reductase,Reductase Inhibitor, Dihydrofolate,Reductase Inhibitors, Dihydrofolate
D005971	Glutamates	Derivatives of GLUTAMIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure.	Glutamic Acid Derivatives,Glutamic Acids,Glutaminic Acids
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man