Abstract 5565: Tumor targeting and enhanced efficacy of novel polyamine-cytotoxic conjugates.
Authors: Liéby-Muller Frédéric , Annereau Jean-Philippe , Brel Viviane , Marion Frédéric , Guminski Yves , Redoules Florence , de Saint Jores Nathalie , André Karine , Kruczynski Anna , Bailly Christian , Guilbaud Nicolas 
Published: August 2014

Abstract
Rapidly proliferating cancer cells have a higher demand on polyamines resulting in an over-activated Polyamines Transport System (PTS)1. Polyamines entry can be exploited as a selective anticancer drug delivery system. We synthesized polyamines-epipodophylotoxin conjugates with improved physico-chemical and pharmacological properties. As proof of concept, we demonstrated that the conjugation of epipodophylotoxin with spermine changes the pharmacological profile of the cytotoxic moiety by increasing the solubility, enhances the cellular distribution through the PTS, and increases the capacity to inhibit topoisomerase II due to stronger DNA interaction, as compared to the closest structurally related compound etoposide. Among several conjugates, F145122 was selected as a drug candidate and is currently undergoing a phase 1/2 clinical evaluation in acute myeloid leukaemia (AML).
Based on this clinically validated objective to target cancer cells with the PTS, we set up a chemical platform of conjugation of polyamine moieties. We extended our approach to 3 natural products of interest in oncology: (i) an inhibitor of elongation phase in protein translation, a modulator of redox cell regulation and an inhibitor of polyADP-ribose polymerase. This approach led to the synthesis of novel spermine-pancratistatine, -artemisinine and -PARPi conjugates and their biochemical and biological characterization in terms of protein synthesis, PARP inhibition, ROS induction, anti-proliferative effects on cancer cells and their capacity to be imported via the PTS. Cell internalisation through the PTS was measured by differential cytotoxicity on PTS+ vs. PTS− cells, or by competition with a fluorescent probe. We also evaluated selected compounds in vivo and investigated whether their modified properties translate into a higher level of antitumor activity associated with an enlarged therapeutic index in a PTS+ tumor model. For the PARP inhibitor-spermine conjugates, an increase in cellular uptake was confirmed, without impairing the cytotoxic properties.
The dedicated polyamine conjugation platform presented here can be adapted to many cytotoxic scaffolds to enhance their solubility, preferential incorporation into cancer cells through the PTS, and their pharmacological activity in vitro and in vivo. The design of polyamine-vectorized cytotoxic agents will be presented.
1 Delcros J.G. et al., Biochem. J., 1993, 269
2 PCT Int. Appl. WO2005/100363 (Pierre Fabre Medicament); Barret J.-M. et al., Cancer Res. 2008, 68, 9845
Citation Format: Frédéric Liéby-Muller, Jean-Philippe Annereau, Viviane Brel, Frédéric Marion, Yves Guminski, Florence Redoules, Nathalie de Saint Jores, Karine André, Anna Kruczynski, Christian Bailly, Nicolas Guilbaud. Tumor targeting and enhanced efficacy of novel polyamine-cytotoxic conjugates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5565. doi:10.1158/1538-7445.AM2013-5565