TY - JOUR

T1 - Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug

AU - Janssen, Samuel

AU - Rosen, D. Marc

AU - Ricklis, Rebecca M.

AU - Dionne, Craig A.

AU - Lilja, Hans

AU - Christensen, Soeren B.

AU - Isaacs, John T.

AU - Denmeade, Samuel R.

PY - 2006/3/1

Y1 - 2006/3/1

N2 - BACKGROUND. Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular 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 μmole/kg) which produced peak serum concentration of ∼36 μM and had a half-life of ∼40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS. The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development.

AB - BACKGROUND. Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular 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 μmole/kg) which produced peak serum concentration of ∼36 μM and had a half-life of ∼40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS. The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development.

KW - Human glandular kallikrein 2 (hK2)

KW - Prodrug

KW - SERCA

KW - Thapsigargin

UR - http://www.scopus.com/inward/record.url?scp=33644765198&partnerID=8YFLogxK

U2 - 10.1002/pros.20348

DO - 10.1002/pros.20348

M3 - Journal article

C2 - 16302271

AN - SCOPUS:33644765198

VL - 66

SP - 358

EP - 368

JO - The Prostate. Supplement

JF - The Prostate. Supplement

SN - 0270-4137

IS - 4

ER -