title: Characterization of the effect of AG337, a novel lipophilic thymidylate synthase inhibitor, on human head and neck and human leukemia cell lines.
abstract: Effects of lipophilic thymidylate synthase (TS) inhibitor AG337 on human head and neck squamous cell carcinoma (HNSCC) cell lines and CCRF-CEM human leukemia cells and sublines with acquired methotrexate (MTX) resistance were assayed using continuous or intermittent drug exposure. During 120-h continuous exposure, HNSCC cell lines A253 and FaDu are equally MTX sensitive (EC50 equals approximately 15nM); AG337 is less potent (EC50 approximately equals 1 microM). A253 is intrinsically resistant to 24-h intermittent MTX exposure (EC50 equals approximately 17 microM; FaDu, EC50 equals approximately 0.3 microM); both HNSCC cell lines are resistant to 24-h AG337 exposure (EC50 >100 microM). CCRF-CEM shows MTX (EC50 =14 nM) and AG337 (EC50 equals approximately 0.6 microM) sensitivity in continuous exposure similar to HNSCC; however, AG337 retains potency against CCRF-CEM cells in intermittent exposure (24-h, EC50 equals approximately 2 microM; 6-h, EC50 equals approximately 48 microM). The reduced folate leucovorin (LV) at > or = 0.1 microM fully protects from growth inhibition by continuous MTX exposure, but growth inhibition by AG337 is reversed only slightly by < or = 100 microM LV. Thymidine fully protects A253 and FaDu against growth inhibition by AG337, while hypoxanthine alone is without effect, suggesting inhibition is TS-specific. CCRF-CEM sublines with acquired MTX-resistance resulting from DHFR overexpression, defective MTX transport, or defective MTX polyglutamylation retain full sensitivity to AG337 in continuous exposure (all EC50 =0.4 microM). These data indicate that AG337 may be useful in therapy of tumors that have acquired resistance to MTX by most common mechanisms.
authors.affiliation: Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: McGuire
authors.forename: J G
authors.initials: JG
authors.lastname: Canestrari
authors.forename: G S
authors.initials: GS
authors.lastname: Nagel
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005312:Fetal Blood / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D002955:Leucovorin / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000378:metabolism / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D003470:Culture Media; D004791:Enzyme Inhibitors; D011799:Quinazolines; D019271:Hypoxanthine; D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; C099178:nolatrexed; D002955:Leucovorin; D013936:Thymidine; D008727:Methotrexate