Baltimore,Maryland

BACKGROUND. Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) andhumanglandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS. In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS. The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 mmole/kg) which produced peak serum concentration of 36 mM and had a half-life of 40min. In addition, over a 24 hr period<0.5%of free L12ADT analogwas observed in plasma. The prodrug demonstrated significant antitumor effect in vivowhile it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins