Role of thymidylate synthase in the antitumor activity of the multitargeted antifolate, LY231514.

摘要: The cytotoxicity of LY231514 was only partially alleviated by thymidine addition (5 microM) in GC3 human colon carcinoma cells, and complete protection required the both hypoxanthine (100 thymidine. In contrast, cytotoxic activity tomudex (raltitrexed, ZD1694) completely reversed alone. MCF-7 breast H630 cells selected for resistance to 5-fluorouracil, respectively via thymidylate synthase (TS) amplification demonstrated modest compared tomudex. LY231514-induced these resistant cell lines prevented microM), indicating inhibition purine de novo biosynthesis as a secondary target action. Thymidine at physiologic levels mouse plasma (approximately 1 produced 2.6-fold shift IC50 LY231514-mediated GC3/cl1 128-fold treatment (i.p., qd x 10) significantly delayed tumor growth xenograft model. However, kinase-deficient mutant this same line heightened sensitivity vivo antitumor with regression established tumors large number tumor-free survivors after one course treatment. data demonstrate that is prominent mechanism LY231514, but important sites action exist multitargeted molecule.