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- Title
F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity.
- Authors
Kruczynski, A; Pillon, A; Créancier, L; Vandenberghe, I; Gomes, B; Brel, V; Fournier, E; Annereau, J-P; Currie, E; Guminski, Y; Bonnet, D; Bailly, C; Guilbaud, N
- Abstract
Chemotherapy remains mainly used for the treatment of acute myeloid leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine moiety facilitates F14512 selective uptake by tumour cells via the polyamine transport system, a machinery overactivated in cancer cells. F14512 has been characterized as a potent drug candidate and is currently in Phase I clinical trials. Here, we demonstrated marked survival benefit and therapeutic efficacy of F14512 treatments in a series of human AML models, established either from AML cell lines or from patient AML samples. Furthermore, we reported in vitro synergistic anti-leukemic effects of F14512 in combination with cytosine arabinoside (Ara-C), doxorubicin, gemcitabine, bortezomib or SAHA. In vivo combination of suboptimal doses of F14512 with Ara-C also resulted in enhanced anti-leukemic activity. We further showed that F14512 triggered both senescence and apoptosis in vivo in primary AML models, but not autophagy. Overall, these results support the clinical development in onco-hematology of this novel promising drug candidate.
- Subjects
POLYAMINES; ANTINEOPLASTIC agents; ACUTE myeloid leukemia treatment; DRUG development; DRUG efficacy; DNA topoisomerases; CANCER cells
- Publication
Leukemia (08876924), 2013, Vol 27, Issue 11, p2139
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2013.108