Abstract 4537: Geranyloxy-ifosfamide: A pre-activated ifosfamide analogue showing an increased therapeutic index

• Published in: Cancer research (Chicago, Ill.) Vol. 75; no. 15_Supplement; p. 4537
• Main Authors: Skarbek, Charles, Desmaele, Didier, Deroussent, Alain, Lesueur, Lea, Daudigeos-Dubus, Estelle, Le Dret, Ludivine, Rivard, Michael, Martens, Thierry, Vassal, Gilles, Couvreur, Patrick, PACI, Angelo
• Format: Journal Article
• Language: English
• Published: 01-08-2015
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-4537

Ifosfamide (IFO) is an alkylating agent used in routine clinical practices for treatment of cancer for many years. As a prodrug it requires cytochrome P450 bio-activation (Giraud et al. Expert Opin.Drug Metab. Toxicol. 2010, 6, 919-938) oxidising the position C-4 leading to the formation of the 4-HO-IFO (10%) which releases of the active compound (isophosphoramide mustard) responsible for the DNA cross links. However, during high dose protocols, this bio-activation leads to the release of two toxic metabolites: i) acrolein, an urotoxic compound, concomitantly generated with the active isophosphoramide mustard and, ii) chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains (Kerbusch et al. Clin Pharmacokinet. 2001, 40, 41-62) responsible for limiting side-effects.
To circumvent these toxic side-effects, we have designed several pre-activated compounds by covalent binding of several O- and S-alkyl moieties on the carbon C-4 to avoid cytochrome bio-activation favoring the release of the 4-HO-IFO, control this release by the physico-chemical properties of the engrafted moiety and limit the chloroacetaldehyde release. Among these designed compounds, some showed a self assembling property leading to nano-assemblies formulation. Moreover, the in vitro evaluation of these compounds in absence of cytochrome has revealed that one of them: the geranyloxy-ifosfamide showed a greater activity under nano-assemblies (600nM) compared to the bulk form (15μM) on rhabdomyosarcoma. This interesting finding has led us to deepen our investigation of this compound to understand and explain the meaning of this increased activity. We present here the latest results obtained for this compound from additional in vitro evaluation on a wide panel of cancer cell line, internalization studies within the cell. Moreover, transmission electron microscopy imaging of this formulation allows the determination of the shape of these nano-assemblies. Previous studies regarding the release kinetic profile of 4-HO-IFO of this compound in vitro in mice plasma at 37°C showed an interesting release profile which was increased when tested as nano-assemblies compared to the bulk form. To validate this finding, a pharmacokinetic study has also been investigated compared to IFO, showing a higher release of 4-HO-IFO compound suggesting that this compound might have an increased therapeutic index. Also, in vivo studies are being carried out at different dose to evaluate the efficacy of this compound (as bulk and nano-assemblies) on rhabdomyosarcoma xenografted mice compared to IFO. These results increase acknowledge of this compound which could become a promising candidate for both oral and IV administration in a wide panel of tumors.
Citation Format: Charles Skarbek, Didier Desmaele, Alain Deroussent, Lea Lesueur, Estelle Daudigeos-Dubus, Ludivine Le Dret, Michael Rivard, Thierry Martens, Gilles Vassal, Patrick Couvreur, Angelo PACI. Geranyloxy-ifosfamide: A pre-activated ifosfamide analogue showing an increased therapeutic index. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4537. doi:10.1158/1538-7445.AM2015-4537