Details

Autor(en) / Beteiligte

• MEYER-LOSIC, Florence
• NICOLAZZI, Céline
• ARRANZ, Valérie
• ZOUBAA, Imane
• FRUCHART, Jean-Sébastien
• RAVEL, Denis
• KEARSEY, Jonathan
• QUINONERO, Jérome
• RIBES, Fabien
• MICHEL, Matthieu
• DUBOIS, Vincent
• DE COUPADE, Catherine
• BOUKAISSI, Matthieu
• CHENE, Anne-Sophie
• TRANCHANT, Isabelle

Titel

DTS-108, A Novel Peptidic Prodrug of SN38: In vivo Efficacy and Toxicokinetic Studies

Ist Teil von

• Clinical cancer research, 2008-04, Vol.14 (7), p.2145-2153

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2008

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Purpose: Irinotecan is a prodrug converted to the active cytotoxic molecule SN38 predominantly by the action of liver carboxylesterases. The efficacy of irinotecan is limited by this hepatic activation that results in a low conversion rate, high interpatient variability, and dose-limiting gastrointestinal toxicity. The purpose of this study was to evaluate a novel peptidic prodrug of SN38 (DTS-108) developed to bypass this hepatic activation and thus reduce the gastrointestinal toxicity and interpatient variability compared with irinotecan. Experimental Design: SN38 was conjugated to a cationic peptide (Vectocell) via an esterase cleavable linker. The preclinical development plan consisted of toxicity and efficacy evaluation in a number of different models and species. Results: The conjugate (DTS-108) is highly soluble, with a human plasma half-life of 400 minutes in vitro . Studies in the dog showed that DTS-108 liberates significantly higher levels of free SN38 than irinotecan without causing gastrointestinal toxicity. In addition, the ratio of the inactive SN38-glucuronide metabolite compared with the active SN38 metabolite is significantly lower following DTS-108 administration, compared with irinotecan, which is consistent with reduced hepatic metabolism. In vivo efficacy studies showed that DTS-108 has improved activity compared with irinotecan. A significant dose-dependent antitumoral efficacy was observed in all models tested and DTS-108 showed synergistic effects in combination with other clinically relevant therapeutic agents. Conclusions: DTS-108 is able to deliver significantly higher levels of SN38 than irinotecan, without the associated toxicity of irinotecan, resulting in an increased therapeutic window for DTS-108 in preclinical models. These encouraging data merit further preclinical and clinical investigation.