Journal
CLINICAL CANCER RESEARCH
Volume 14, Issue 7, Pages 2145-2153Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-07-4580
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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 pepticlic 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-glucuronicle 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.
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