This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barret, J.-M. Articles by Bailly, C. Search for Related Content PubMed PubMed Citation Articles by Barret, J.-M. Articles by Bailly, C.

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

¹ Centre de Recherche en Oncologie Expérimentale, Toulouse, France; ² Division de Chimie Médicinale III, Centre de Recherche Pierre Fabre, Castres, France; ³ Groupe Cycle Cellulaire, Centre National de la Recherche Scientifique UMR6061, IFR 97, Faculté de Médecine, Université de Rennes I, Rennes, France; and ⁴ Institut National de la Sante et de la Recherche Medicale U-837, COL, Institut de Recherche sur le Cancer, Lille, France

Requests for reprints: Jean-Marc Barret, Centre de Recherche en Oncologie Expérimentale-Institut de Recherche Pierre Fabre, 3 rue des satellites-BP 94244, 31432 Toulouse cedex 4, France. Phone: 33-534-32-14-44; Fax: 33-534-32-14-34; E-mail: jean.marc.barret{at}pierre-fabre.com.

Key Words: F14512 • polyamine transport • spermine • targeted drug • antitumor agent • topoisomerase II • tumor regression

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 µmol/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. [Cancer Res 2008;68(23):9845–53]

This article has been cited by other articles:

				N. F. Evageliou and M. D. Hogarty Disrupting Polyamine Homeostasis as a Therapeutic Strategy for Neuroblastoma Clin. Cancer Res., October 1, 2009; 15(19): 5956 - 5961. [Abstract] [Full Text] [PDF]