Abstract 2747: Synergistic antileukemic activity of F14512 in combination with AraC

Abstract

Abstract New antileukemic agents are urgently needed to achieve improvement of the survival of patients suffering from Acute Myelogenous Leukemia (AML). F14512 combines an epipodophyllotoxin core with a spermine moiety that targets cells with a high demand for polyamines such as cancer cells. F14512 exhibits a high level of in vivo anti-tumor activity in a series of experimental murine and human solid tumor models and has entered into clinical phase one. In this study, we investigated the in vivo antileukemic activity of F14512 against cell line or primary human AML models and evaluated its potential in combination with the reference antileukemic agent, AraC. HL60 cells or AML cells collected from different patients were engrafted onto NSG mice. Using flow cytometry and q-PCR analysis, we demonstrated that multiple administrations of F14512 for 3 weeks resulted in an extensive reduction of AML cell number in the bone marrow and blood of treated mice. We also showed in vitro and in vivo synergistic activity of F14512 in combination with AraC in HL-60 and primary AML models when both compounds were used at suboptimal doses. The mechanisms triggering primary leukemic cell death were investigated and our results indicated that senescence could be involved. Collectively, these results demonstrate that F14512 exhibits a marked in vivo antileukemic activity, supporting the Phase I clinical trials of this novel promising drug candidate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2747. doi:1538-7445.AM2012-2747