title: F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system.
abstract: 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.
authors.affiliation: Centre de Recherche en Oncologie Expérimentale, Toulouse, France. jean.marc.barret@pierre-fabre.com
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Barret
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.forename: Stéphane
authors.initials: S
authors.lastname: Vispé
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Annereau
authors.forename: Viviane
authors.initials: V
authors.lastname: Brel
authors.forename: Yves
authors.initials: Y
authors.lastname: Guminski
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Delcros
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilbaud
authors.forename: Thierry
authors.initials: T
authors.lastname: Imbert
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015317:Biogenic Polyamines / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D016503:Drug Delivery Systems; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D015317:Biogenic Polyamines; D004273:DNA, Neoplasm; C534191:F14512; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin