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.