Raltitrexed

A quinazoline antifolate thymidylate synthase (TS) inhibitor with Ki of 62 nM; inhibits TS with IC50 of 2.5 nM and L1210 tumor cell growth with IC50 of 8 nM; acitve in vivo.Chemotherapeutic Agents Approved (In Vitro) :Raltitrexed inhibits HepG2 proliferation by arresting the cell cycle at G0/G1, and the cell cycle is mediated via downregulation of cyclin A and CDK2. Raltitrexed (0.1, 0.5, 2.5 μg/mL) decreases the viability of SGC7901 cells in a dose- and time-dependent manner. Raltitrexed (0.5 μg/mL) shows typical apoptotic morphology, including nuclear shrinkage, fragmentation, chromatin condensation and apoptotic bodies in SGC7901 cells. Raltitrexed blocks the cell cycle at the G0/G1 phase, decreases in the mitochondrial membrane potential. Raltitrexed also increases the level of ROS, induces caspase-3-dependent apoptosis via activation of the mitochondria, and increases TS protein and mRNA expression levels. Raltitrexed (1.5 nM) reduces the number of GM00637 cells, selectively induces gene conversions, but does not affect DSB-induced HR or NHEJ. (In Vivo) :Raltitrexed (0, 5, 10, 11.5, 13.5, 15 mg/kg b/w, i.p.) increases the rates of resorbed embryos and growth retardation of murine model of NTDs in a dose dependent manner. Raltitrexed (11.5 mg/kg b/w) maximally inhibits the thymidylate synthase (TS) activity in embryonic tissue, decreases dTMP levels and while increases dUMP levels.