Biomaterial Database

Cytotoxic effects of folate antagonists against methotrexate-resistant human leukemic lymphoblast CCRF-CEM cell lines. 1985

E Mini, and B A Moroson, and C T Franco, and J R Bertino

A human T-lymphoblast cell line, CCRF-CEM/R1, resistant to methotrexate by virtue of increased dihydrofolate reductase activity, was grown in stepwise increasing concentrations of methotrexate. This additional selection pressure resulted in a cell line, CCRF-CEM/R2, resistant to methotrexate by virtue of both an elevation of dihydrofolate reductase activity and a marked decrease in methotrexate transport. The R1 and R2 cells were approximately 70- and 350-fold more resistant to methotrexate than were the parent cells. The effects of three folate antagonists were studied on these cell lines and also on CCRF-CEM/R3 cells, characterized by impaired methotrexate transport but normal levels of dihydrofolate reductase. The elevated reductase subline CCRF-CEM/R1 was cross-resistant to triazinate [Baker's antifol, NSC 139105; ethanesulfonic acid compounded with alpha-(2-chloro-4-[4,6-diamino-2,2-dimethyl-S-triazine-1-(2H)-yl] phenoxyl)-N,N-dimethyl-m-toluamide (1:1)] and trimetrexate (NSC 249008, JB-11, TMQ; 2,4-diamino-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline), two nonclassical folate antagonists. In contrast, the transport defective subline, CCRF-CEM/R3 was not cross-resistant to these two compounds. In cells resistant to MTX by virtue of both mechanisms, CCRF-CEM/R2, triazinate, and trimetrexate were partially cross-resistant. All three methotrexate-resistant sublines showed minor cross-resistance to isoaminohydroxyquinazoline (IAHQ, NSC 289517; 5,8-dideazaisopteroylglutamate), a folate antagonist inhibitor of thymidylate synthase. These data demonstrate that methotrexate-resistant tumor cells may be effectively inhibited by antifolates with different route of entry into cells or with different enzyme targets.

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D007945	Leukemia, Lymphoid	Leukemia associated with HYPERPLASIA of the lymphoid tissues and increased numbers of circulating malignant LYMPHOCYTES and lymphoblasts.	Leukemia, Lymphocytic,Lymphocytic Leukemia,Lymphoid Leukemia,Leukemias, Lymphocytic,Leukemias, Lymphoid,Lymphocytic Leukemias,Lymphoid Leukemias
D008727	Methotrexate	An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.	Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D002455	Cell Division	The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.	M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
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
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
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970	Antineoplastic Agents	Substances that inhibit or prevent the proliferation of NEOPLASMS.	Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships