Enzymatice Activation of Proteasome Inhibitor Prodrugs by Prostate-Specific Antigen as Targeted Therapy for Prostate Cancer
Abstract
The aim of this proposal is to develop a method to target novel cytotoxic agents specifically to sites of metastatic prostate cancer. In the original proposal, proteasome inhibitors were selected as the cytotoxic agent. Initial studies revealed that this approach was not tenable due to the inherent instability of these compounds. An alternative agent was then selected to continue this targeted prodrug approach. Thapsigargin (TG) induces apoptosis in a proliferation independent manner in prostate cancer cells. This cytotoxicity, however, is not prostate cell type specific and TG could not be given systemically without significant toxicity. To achieve targeted cytotoxicity the TG analogs will be converted to inactive prodrugs by coupling to a peptide carrier that is a substrate for the serine protease activity of Prostate-Specific Antigen (PSA). Since PSA is expressed in high levels only by normal and malignant prostate cells, this approach should allow specific targeting of the killing ability of TC to prostate cancer cells. Therefore a series of amine containing TC analogs have been synthesized and characterized for their ability to induce apoptosis in prostate cancer cell lines. The lead TC analog has been chemically linked via a peptide bond to a previously identified PSA-specific peptide (i.e. 6 amino acids) to produce an inactive prodrug. This prodrug can be hydrolyzed by PSA and a 25-fold increase in toxicity is seen in the presence of enzymatically active PSA. In vivo studies using this lead TC prodrug to treat PSA-producing human prostate cancers are underway. Additional prodrugs will also be synthesized in order to optimize PSA-targeting.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2001
- Accession Number
- ADA406091
Entities
People
- Samuel Denmeade
Organizations
- Johns Hopkins University