title: DTS-108, a novel peptidic prodrug of SN38: in vivo efficacy and toxicokinetic studies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Diatos S.A., Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Meyer-Losic
authors.forename: Céline
authors.initials: C
authors.lastname: Nicolazzi
authors.forename: Jérôme
authors.initials: J
authors.lastname: Quinonero
authors.forename: Fabien
authors.initials: F
authors.lastname: Ribes
authors.forename: Matthieu
authors.initials: M
authors.lastname: Michel
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubois
authors.forename: Catherine
authors.initials: C
authors.lastname: de Coupade
authors.forename: Matthieu
authors.initials: M
authors.lastname: Boukaissi
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Chéné
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tranchant
authors.forename: Valérie
authors.initials: V
authors.lastname: Arranz
authors.forename: Imane
authors.initials: I
authors.lastname: Zoubaa
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Fruchart
authors.forename: Denis
authors.initials: D
authors.lastname: Ravel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kearsey
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002412:Cations; D004285:Dogs; D004337:Drug Carriers; D006801:Humans; D000077146:Irinotecan; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002412:Cations; C529642:DTS-108; D004337:Drug Carriers; D010455:Peptides; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin