F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system. - Archive ouverte HAL Access content directly
Journal Articles Cancer Research Year : 2008

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

(1) , (1) , (1) , (1) , (1) , (2) , (3) , (4) , (1) , (2) , (1)
1
2
3
4

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.

Dates and versions

inserm-00353546 , version 1 (15-01-2009)

Identifiers

Cite

Jean-Marc Barret, Anna Kruczynski, Stéphane Vispé, Jean-Philippe Annereau, Viviane Brel, et al.. F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system.. Cancer Research, 2008, 68 (23), pp.9845-53. ⟨10.1158/0008-5472.CAN-08-2748⟩. ⟨inserm-00353546⟩
219 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More