F14512 is a novel anti-
tumor molecule based on an
epipodophyllotoxin core coupled to a
cancer-cell vectoring
spermine moiety. This
polyamine linkage is assumed to ensure the preferential uptake of
F14512 by
cancer cells, strong interaction with
DNA and potent inhibition of
topoisomerase II (
Topo II). The antitumor activity of
F14512 in human
tumor models is significantly higher than that of other epipodophyllotoxins in spite of a lower induction of
DNA breakage. Hence, the demonstrated superiority of
F14512 over other
Topo II
poisons might not result solely from its preferential uptake by
cancer cells, but could also be due to unique effects on
Topo II interactions with
DNA. To further dissect the mechanism of action of
F14512, we used Drosophila melanogaster mutants whose genetic background leads to an easily scored phenotype that is sensitive to changes in
Topo II activity and/or localization.
F14512 has antiproliferative properties in Drosophila cells and stabilizes ternary
Topo II/
DNA cleavable complexes at unique sites located in moderately repeated sequences, suggesting that the drug specifically targets a select and limited subset of genomic sequences. Feeding
F14512 to developing mutant Drosophila larvae led to the recovery of flies expressing a striking phenotype, "Eye wide shut," where one eye is replaced by a first thoracic segment. Other recovered F14512-induced gain- and loss-of-function phenotypes similarly correspond to precise genetic dysfunctions. These complex in vivo results obtained in a whole developing organism can be reconciled with known genetic anomalies and constitute a remarkable instance of specific alterations of gene expression by ingestion of a drug. "Drosophila-based anticancer pharmacology" hence reveals unique properties for
F14512, demonstrating the usefulness of an assay system that provides a low-cost, rapid and effective
complement to mammalian models and permits the elucidation of fundamental mechanisms of action of candidate drugs of therapeutic interest in humans.