Abstract LB-38: Evaluation of a PSA cleavable doxorubicin prodrug in the in vitro and in vivo LNCaP LN model

Abstract

Abstract The goal of this work was to investigate the biological activity of a doxorubicin prodrug that is efficiently cleaved by prostate specific antigen (PSA) rapidly liberating doxorubicin as the final cleavage product. For this purpose we have developed an albumin-binding prodrug of doxorubicin, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Leu-PABC-DOXO [EMC: ε-maleimidocaproyl; PABC: p-aminobenzyloxycarbonyl; DOXO: doxorubicin]. The incorporation of the PABC self-eliminating linker between the peptide sequence and doxorubicin enhanced the enzymatic cleavage rate and improved the cleavage profile. PSA cleavage produced the metabolite H-Ser-Leu-PABC-DOXO which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. In the cell culture experiments, our prodrug exhibited antiproliferative activity in the low micromolar range with an IC50 value of ∼1 μM against a PSA-expressing prostate cancer cell line with a stably integrated Luciferase-Neomycin (LN) resistance fusion gene cassette (LNCaP LN). Moreover, H-Ser-Leu-PABC-DOXO showed comparable in vitro activity to doxorubicin (∼0.2 μM). Orientating toxicity studies in mice showed that the maximum tolerated dose of our novel prodrug was twice that of conventional doxorubicin. Consequently, the in vivo efficacy of the prodrug (6 mg/kg doxorubicin equivalents) is currently being compared to free doxorubicin (3 mg/kg) in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-38.