title: Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity.
abstract: Acute myeloid leukemia (AML) is an aggressive malignancy that leads to marrow failure and death. There is a desperate need for new therapies. The novel fluoropyrimidine, FdUMP[10], was highly active against both human AML cell lines, (IC(50) values, 3.4nM-21.5nM) and murine lines (IC(50) values, 123.8pM-131.4pM). In all cases, the IC(50) of FdUMP[10] was lower than for cytarabine and ∼ 1000 times lower than 5-fluorouracil (5-FU). FdUMP[10] remained effective against cells expressing the Flt3 internal tandem duplication, BCR-ABL, MN1, and an shRNA against p53. It had activity against patient samples at concentrations that did not affect normal hematopoietic cells. FdUMP[10] inhibited thymidylate synthase (TS) and trapped topoisomerase I cleavage complexes (Top1CCs), leading to DNA damage and apoptosis. All cell lines and nearly all primary AML samples examined expressed both TS and Top1. In vivo, FdUMP[10] was active against a syngeneic AML model with a survival advantage equivalent to doxorubicin plus cytarabine. 5-FU treatment was toxic and did not improve survival. FdUMP[10] was better tolerated than 5-FU or cytarabine plus doxorubicin and did not affect normal HSCs, while 5-FU dramatically impaired their ability to engraft. In summary, FdUMP[10] was highly efficacious and better tolerated than standard therapies.
authors.affiliation: Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. tspardee@wakehealth.edu
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Pardee
authors.forename: Evan
authors.initials: E
authors.lastname: Gomes
authors.forename: Jamie
authors.initials: J
authors.lastname: Jennings-Gee
authors.forename: David
authors.initials: D
authors.lastname: Caudell
authors.forename: William H
authors.initials: WH
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D005468:Fluorodeoxyuridylate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D059004:Topoisomerase I Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C435305:FdUMP(10); D059004:Topoisomerase I Inhibitors; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D004264:DNA Topoisomerases, Type I