Enzymatic Activation of Proteasome Inhibitor Prodrugs by Prostate-Specific Antigen as Targeted Therapy for Prostate Cancer
Final rept. 1 Dec 1999-30 Nov 2002
JOHNS HOPKINS UNIV BALTIMORE MD
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The aim of this proposal is to develop a method to target novel cytotoxic agents specifically to sites of metastatic prostate cancer. 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 were 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 allows specific targeting of the killing ability of TG to prostate cancer cells, A series of amine containing TG analogs were synthesized and characterized for their ability to induce apoptosis in prostate cancer cell lines. The lead TO analog was 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 is hydrolyzed by PSA and is selectively toxic to PSA- producing prostate cancer cells in vitro and in vivo. On the basis of these studies, further clinical development of PSA-activated TO proddrug is warranted.
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