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Ref Type Journal Article
PMID (19047165)
Authors Barret JM, Kruczynski A, Vispe S, Annereau JP, Brel V, Guminski Y, Delcros JG, Lansiaux A, Guilbaud N, Imbert T, Bailly C
Title F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system.
Journal Cancer research
Vol 68
Issue 23
Date 2008 Dec 1
URL
Abstract Text The polyamine transport system (PTS) is an energy-dependent machinery frequently overactivated in cancer cells with a high demand for polyamines. We have exploited the PTS to selectively deliver a polyamine-containing drug to cancer cells. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a water-soluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS. F14512 is 73-fold more cytotoxic to Chinese hamster ovary cells compared with CHO-MG cells with a reduced PTS activity. A decreased sensitivity of L1210 leukemia cells to F14512 was observed in the presence of putrescine, spermidine, and spermine. In parallel, the spermine moiety considerably enhances the drug-DNA interaction, leading to a reinforced inhibition of topoisomerase II. The spermine tail of F14512 serves as a cell delivery vehicle as well as a DNA anchor, and this property translates at the cellular level into a distinct pharmacologic profile. Twenty-nine human solid or hematologic cell lines were used to characterize the high cytotoxic potential of F14512 (median IC50 of 0.18 micromol/L). Finally, the potent antitumor activity of F14512 in vivo was evidenced with a MX1 human breast tumor xenograft model, with partial and complete tumor regressions. This work supports the clinical development of F14512 as a novel targeted cytotoxic drug and sheds light on the concept of selective delivery of drugs to tumor cells expressing the PTS.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
F14512 F14512 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
F14512 F-14512 TOPO2 inhibitor 4 F14512 is composed of a derivative of the topoisomerase II inhibitor etoposide linked to a spermidine chain, which enables cellular uptake through the polyamine transport system, resulting in increased DNA damage and decreased tumor growth (PMID: 19047165, PMID: 30547316).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown breast cancer not applicable F14512 Preclinical - Cell line xenograft Actionable In a preclinical study, F14512 induced tumor regression in breast cancer cell line xenograft models (PMID: 19047165). 19047165
Unknown unknown Advanced Solid Tumor not applicable F14512 Preclinical Actionable In a preclinical study, F14512 inhibited growth of a variety of human solid tumor cell lines in culture (PMID: 19047165). 19047165