Characterization of the effect of AG337, a novel lipophilic thymidylate synthase inhibitor, on human head and neck and human leukemia cell lines.
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.
McGuire
J J
JJ
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Canestrari
J G
JG
Nagel
G S
GS
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
D003470:Culture Media; D004791:Enzyme Inhibitors; D011799:Quinazolines; D019271:Hypoxanthine; D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; C099178:nolatrexed; D002955:Leucovorin; D013936:Thymidine; D008727:Methotrexate