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

Samuel Janssen, D. Marc Rosen, Rebecca M. Ricklis, Craig A. Dionne, Hans Lilja, Soeren B. Christensen, John Tod Isaacs, Samuel R Denmeade

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)358-368
Number of pages11
JournalProstate
Volume66
Issue number4
DOIs
StatePublished - Mar 1 2006

Fingerprint

Tissue Kallikreins
Thapsigargin
Prodrugs
Pharmacokinetics
Prostatic Neoplasms
Peptide Library
Peptides
Maximum Tolerated Dose
Poisons
Cytotoxins
Prostate-Specific Antigen
Toxicology
Half-Life
Hydrolysis
Peptide Hydrolases
Serum

Keywords

  • Human glandular kallikrein 2 (hK2)
  • Prodrug
  • SERCA
  • Thapsigargin

ASJC Scopus subject areas

  • Urology

Cite this

Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug. / Janssen, Samuel; Rosen, D. Marc; Ricklis, Rebecca M.; Dionne, Craig A.; Lilja, Hans; Christensen, Soeren B.; Isaacs, John Tod; Denmeade, Samuel R.

In: Prostate, Vol. 66, No. 4, 01.03.2006, p. 358-368.

Research output: Contribution to journalArticle

Janssen, Samuel ; Rosen, D. Marc ; Ricklis, Rebecca M. ; Dionne, Craig A. ; Lilja, Hans ; Christensen, Soeren B. ; Isaacs, John Tod ; Denmeade, Samuel R. / Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug. In: Prostate. 2006 ; Vol. 66, No. 4. pp. 358-368.
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