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F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system.

Authors
  • Barret, Jean-Marc
  • Kruczynski, Anna
  • Vispé, Stéphane
  • Annereau, Jean-Philippe
  • Brel, Viviane
  • Guminski, Yves
  • Delcros, Jean-Guy
  • Lansiaux, Amélie
  • Guilbaud, Nicolas
  • Imbert, Thierry
  • Bailly, Christian
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Dec 01, 2008
Volume
68
Issue
23
Pages
9845–9853
Identifiers
DOI: 10.1158/0008-5472.CAN-08-2748
PMID: 19047165
Source
Medline
License
Unknown

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.

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