In vivo activity of a PSA-activated doxorubicin prodrug against PSA-producing human prostate cancer xenografts

BACKGROUND. There is currently no effective therapy for men with metastatic prostate cancer who relapse after androgen ablation. Prolonged administrat ion of effective concentrations of standard chemotherapeutic agents is usua lly nut possible because of dose-limiting systemic toxicities. A new strate gy to target cytotoxic agents specifically to sites of metastatic prostate cancer while avoiding systemic toxicity would be to develop prodrugs that a re inactive when given systemically but become activated when processed pro teolytically within prostate cancer metastases by prostate-specific antigen (PSA). In this study, the in vivo activity of a prodrug consisting of doxo rubicin (Dox) conjugated to a PSA-specifie peptide carrier is described. METHODS. Nude mice bearing PSA-producing human prostate cancer xenografts w ere treated either intraperitoneally (IP) or by continuous infusion with th e Dox prodrug. Toxicity (weight loss, death) and antitumor efficacy (tumor volume changes) were determined. RESULTS. The PSA-peptide Dox prodrug had no discernible systemic toxicity w hen given at four times the 100% lethal Dox equivalent dose. An IP dose of 60 mg/kg/week x 4 weeks resulted in a 57% decrease in tumor weight vs. cont rol after 40 days. A 25 mg/kg/week dose given by continuous infusion produc ed a similar decrease in tumor weight vs. control. CONCLUSIONS. The PSA-specific peptide/doxorubicin prodrug can be used to de liver higher intratumoral levels of Dox for longer duration while avoiding systemic toxicity. In addition, these results validate the specificity of t he PSA-specific peptide as a targetable drug carrier. This PSA-specific pep tide could also be used as a carrier to target a wide variety of cytotoxic agents for specific activation within sites of metastatic prostate cancer. (C) 2000 Wiley-Liss, Inc.