Replication-dependent irreversible topoisomerase 1 poisoning is responsible for FdUMP[10] anti-leukemic activity.

ABSTRACT: Previous studies have indicated that 5-Fluoro-2'-deoxyuridine-5'-O-monophosphate 10mer (FdUMP[10]) displays strong antileukemic activity through the dual targeting of thymidylate synthase (TS) and DNA topoisomerase 1 (Top1). The present studies were undertaken to clarify the relationship between the induction of a thymineless state and the formation of Top1 cleavage complexes (Top1CC) for inducing cell death and to clarify the role of DNA replication for induction of lethal DNA double-strand breaks (DSBs) in FdUMP[10]-treated acute myeloid leukemia (AML) cells. Human promyelocytic (HL60) and AML (KG1a, Molm13, THP-1) cells were synchronized by serum starvation and treated with FdUMP[10] with thymidine (Thy) rescue. Cells were assayed for TS inhibition, DNA DSBs, Top1CC, and apoptosis to cl

SUBMITTER: Jennings-Gee J 

PROVIDER: S-EPMC3660094 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature