Abstract 3799: Polyamine Transport System (PTS) activity and hijacking in cancer cells: New option in Head and Neck tumors treatment with the polyamine-containing drug candidate F14512

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.3799-3799
• Main Authors: Meignan, Samuel, Mouawad, Francois, Dewitte, Amelie, Bertheau, Charlotte, Wattez, Nicole, Gros, Abigaelle, Lartigau, Eric, Chevalier, Dominique, Bailly, Christian, Lansiaux, Amelie
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-3799

The Polyamine Transport System, although not clearly identified at the molecular level in eukaryotic organisms, was found over activated in many types of cancer cells, such as leukemia, prostate, melanoma and NSCLC. Polyamines are implicated in many biological functions, and the need for polyamines in tumor cells, conveyed by the PTS, is crucial. New therapeutic strategies consist to use this transport system to deliver a cytotoxic agent specifically into cancer cells. Head and neck cancer remains the 6th common cancer with a very poor survival rate indicating the crucial need for new targeted strategies. For this study, we used 4 Head and Neck (H & N) cancer cell lines representative of various localizations: CAL 33 and CAL 27 from base of the tongue, Fadu from the pharynx and SQ20B from the larynx. Here, using a polyamine-coupled fluorescent probe, we show that the PTS is active in all head and neck cancer cell lines regardless the tumor localization. In these models, flow cytometry demonstrated that the PTS incorporates quickly, massively and specifically the probe into cancer cells. Confocal microscopy observations revealed that the spermine probe accumulates into the cell nuclei, the site of action of F14512 which is a potent topoisomerase II inhibitor. Considering this property, we evaluated the potential of the F14512 (Pierre Fabre laboratories, France) in these H & N cancer cell lines. F14512 contains a PTS-recognized spermine side chain attached to an epipodophyllotoxin moiety targeting topoisomerase II. We found that F14512 presents a much higher cytotoxicity than etoposide in the 4 cell lines. Competition assays showed that this effect is dependent of the PTS activity and confirmed the targeted action of F14512 against cells with active PTS. The high efficiency of F14512 in the head and neck cancer cell lines is reported here for the first time and may be of interest for the future development of this novel drug candidate, currently in phase 1 clinical trial in leukemia. Studies are in progress, using fresh tumor biopsies from patients with head and neck cancer, to analyze the PTS status of the tumors using the specific spermine-containing fluorescent probe and to evaluate the activity of F14512. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3799.