F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity.

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.

• Authors: A Kruczynski, A Pillon, L Créancier, I Vandenberghe, B Gomes, V Brel, E Fournier, J-P Annereau, E Currie, Y Guminski, D Bonnet, C Bailly, N Guilbaud
• Journal: Leukemia (Leukemia) Vol. 27 Issue 11 Pg. 2139-48 (Nov 2013) ISSN: 1476-5551 [Electronic] England
• PMID: 23568148 (Publication Type: Journal Article)

Chemical References

• Boronic Acids
• F14512
• Hydroxamic Acids
• Il2rg protein, mouse
• Interleukin Receptor Common gamma Subunit
• Pyrazines
• RNA, Messenger
• Cytarabine
• Deoxycytidine
• Vorinostat
• Bortezomib
• Doxorubicin
• Podophyllotoxin
• Gemcitabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Boronic Acids (administration & dosage)
• Bortezomib
• Cell Proliferation (drug effects)
• Cytarabine (administration & dosage)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Doxorubicin (administration & dosage)
• Fetal Blood (cytology, drug effects)
• Flow Cytometry
• Humans
• Hydroxamic Acids (administration & dosage)
• Immunoenzyme Techniques
• Interleukin Receptor Common gamma Subunit (physiology)
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Podophyllotoxin (administration & dosage, analogs & derivatives)
• Pyrazines (administration & dosage)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tumor Cells, Cultured
• Vorinostat
• Xenograft Model Antitumor Assays
• Gemcitabine