title: F14512, a polyamine-vectorized inhibitor of topoisomerase II, exhibits a marked anti-tumor activity in ovarian cancer.
abstract: Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women and frequently associated with carboplatin resistance, underlining the need for more efficient and targeted therapies. F14512 is an epipodophylotoxin-core linked to a spermine chain which enters cells via the polyamine transport system (PTS). Here, we investigate this novel concept of vectorization in ovarian cancer. We compared the effects of etoposide and F14512 on a panel of five carboplatin-sensitive or resistant ovarian cancer models. We assessed the incorporation of F17073, a spermine-linked fluorescent probe, in these cells and in 18 clinical samples. We then showed that F14512 exhibits a high anti-proliferative and pro-apoptotic activity, particularly in cells with high levels of F17073 incorporation. Consistently, F14512 significantly inhibited tumor growth compared to etoposide, in a cisplatin-resistant A2780R subcutaneous model, at a dose of 1.25 mg/kg. In addition, ex vivo analysis indicated that 15 out of 18 patients presented a higher F17073 incorporation into tumor cells compared to normal cells. Overall, our data suggest that F14512, a targeted drug with a potent anti-tumor efficacy, constitutes a potential new therapy for highly PTS-positive and platinum-resistant ovarian cancer-bearing patients.
authors.affiliation: EA4553, IUCT-Oncopole, 1 avenue Irène Joliot-Curie, 31059 Toulouse, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Thibault
authors.affiliation: EA4553, IUCT-Oncopole, 1 avenue Irène Joliot-Curie, 31059 Toulouse, France.
authors.forename: Emily
authors.initials: E
authors.lastname: Clement
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Zorza
authors.affiliation: Centre Oscar Lambret, INSERM, 3 rue Frédéric Combemale, 9000 Lille, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Meignan
authors.affiliation: EA4553, IUCT-Oncopole, 1 avenue Irène Joliot-Curie, 31059 Toulouse, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.affiliation: EA4553, IUCT-Oncopole, 1 avenue Irène Joliot-Curie, 31059 Toulouse, France. Electronic address: Couderc.bettina@iuct-oncopole.fr.
authors.forename: Bettina
authors.initials: B
authors.lastname: Couderc
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.affiliation: Centre Oscar Lambret, INSERM, 3 rue Frédéric Combemale, 9000 Lille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Narducci
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vandenberghe
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilbaud
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ferré
authors.affiliation: Centre de recherche et développement Pierre Fabre, 2 avenue Hubert Curien, 31562 Toulouse, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Annereau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015317:Biogenic Polyamines / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; C534191:F14512; D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin
keywords: Ovarian cancer; Polyamine transport system; Topoisomerase II inhibitor