Enzymatic Activation of Peptide Prodrugs by Prostate-Specific Membrane Antigen (PSMA) as Targeted Therapy for Prostate Cancer
Final rept. 1 Jan 2004-31 Dec 2004
JOHNS HOPKINS UNIV BALTIMORE MD
Pagination or Media Count:
The majority of our present chemotherapeutic agents only kill cells effectively when they are proliferating this may explain why these agents have been of such limited success in patients. In contrast to these ineffective agents we have chemically modified a plant toxin Thapsigargin TG to produce primary amine-containing analogs that are potent cell proliferation independent inducers of apoptosis in prostate cancer cells. These TG-analogs however are not prostate cancer-specific cytotoxins. The hypothesis is that a potent TG analog can be converted to an inactive prodrug by coupling to a peptide carrier that is a substrate for Prostate Specific Membrane Antigen PSMA. Since PSMA is expressed in high levels only by prostate cancer cells and not by normal cells this should allow specific targeting of the TG- analogs killing ability to prostate cancer cells thus minimizing toxicity to normal tissue. Two enzymatic activities for PSMA have been described an N-acetyl- linked acid dipeptidase NAALADase activity and a pteroyl poly-y-glutamyl carboxypeptidase folate hydrolase activity. On the basis of preliminary data the ideal TG prodrug should consist of either an aspartate or glutamate containing TG analog coupled via to a peptide containing a series of alpha- and y-linked glutamates and ending in an alpha-linked aspartyl-glutamate cap. This substrate would be readily cleaved by PSMA but would be stable to hydrolysis by proteases such as gamma-glutamyl hydrolase present in serum and extracellular fluid of some normal tissue types.
- Anatomy and Physiology
- Medicine and Medical Research