Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity
Menée in vitro et in vivo, cette étude évalue l'activité et la toxicité d'une nouvelle fluoropyrimidine, FdUMP[10], pour le traitement d'une leucémie myéloïde aiguë
Acute Myeloid Leukemia 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, (IC50 values 3.4 - 21.5 nM) and murine lines (IC50 values 123.8 to 131.4 pM). In all cases, the IC50 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 ITD, BCR-ABL, MN1 and an shRNA against p53. It had activity against patient samples at concentrations that did not impact normal hematopoietic cells. FdUMP[10] inhibited thymidylate synthase (TS) and trapped topoisomerase I cleavage complexes (Top1CC) 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 hematopoietic stem cells (HSCs) while 5-FU dramatically impaired their ability to engraft. In summary, FdUMP[10] was highly efficacious and better tolerated than standard therapies.