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|Ref Type||Journal Article|
|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.|
|Date||2008 Dec 1|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|