Approximately forty thousand American men die annually from metastatic prostate cancer. Standard chemotherapeutic agents have been ineffective at significantly prolonging the survival of men with metastatic prostate cancer and these agents are typically associated with often severe, dose-limiting side effects. New agents are therefore urgently needed. While a large number of cytotoxic agents have been demonstrated to be effective in vitro, these agents are typically general cytotoxins that cannot be administered to patients without severe systemic toxicities. Therefore, what is required is a method to target the delivery of novel, effective cytotoxic agents specifically to sites of metastatic prostate cancer. Such an approach would result in increased concentration of drug within the tumor while avoiding significant systemic toxicity. One such novel class of agents that has been demonstrated in recent studies to induce apoptosis in a variety of cell types, including prostate cancers, are doxirubicin and thapsigargin analogues. Other classes of anticancer agents such as taxol or taxotere and rhodamine 123 have shown promising therapeutic efficacy for the management of human cancer. These anticancer agents, therefore, represent a potentially novel approach toward the treatment of metastatic prostate cancer. The cytotoxicity of these agents, however, is not prostate cancer specific. In this proposal, a prostate cancer specific targeting strategy is outlined that will overcome this limitation. To achieve targeted cytotoxicity, these compounds will be converted to biologically inactive prodrugs by coupling to a peptide carrier or peptide linked with spacer group such that they can be efficiently converted back to active killing agents only upon proteolysis by the serine protease activity of a unique prostate-specific protein, Prostate-Specific Antigen (PSA). Since PSA is expressed in high levels only by normal and malignant prostate cells and not in any significant amounts by other normal cell types, this approach should allow specific targeting of the killing ability of these agents to prostate cancer cells Therefore, a series of amine containing thapsigargin analogue, taxol or taxotere, and rhodamine 123 will be synthesized and characterized. These cytotoxic agents will be chemically linked via a peptide bond to a previously identified PSA-specific peptide to produce inactive prodrugs. Prodrugs will be tested for their potency and selectivity as PSA activated killing agents against PSA-producing, androgen independent human prostate cancer cells. The lead prodrug will then be tested in vivo for activity in mice bearing PSA-producing human prostate cancers. These studies will serve to identify the best candidate prodrug that will be subsequently tested in clinical trials as treatment for metastatic prostate cancer.
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