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 administration of effective concentrations of standard chemotherapeutic agents is usually not possible because of dose-limiting systemic toxicities. A new strategy to target cytotoxic agents specifically to sites of metastatic prostate cancer while avoiding systemic toxicity would be to develop prodrugs that are inactive when given systemically but become activated when processed proteolytically within prostate cancer metastases by prostate-specific antigen (PSA). In this study, the in vivo activity of a prodrug consisting of doxorubicin (Dox) conjugated to a PSA-specific peptide carrier is described.


METHODS
Nude mice bearing PSA-producing human prostate cancer xenografts were treated either intraperitoneally (IP) or by continuous infusion with the 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 when 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. control after 40 days. A 25 mg/kg/week dose given by continuous infusion produced a similar decrease in tumor weight vs. control.


CONCLUSIONS
The PSA-specific peptide/doxorubicin prodrug can be used to deliver higher intratumoral levels of Dox for longer duration while avoiding systemic toxicity. In addition, these results validate the specificity of the PSA-specific peptide as a targetable drug carrier. This PSA-specific peptide could also be used as a carrier to target a wide variety of cytotoxic agents for specific activation within sites of metastatic prostate cancer.
Khan
S R
SR
The Johns Hopkins Oncology Center, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231-1001, USA.
Denmeade
S R
SR
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D013379:Substrate Specificity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009842:Oligopeptides; D011355:Prodrugs; C413288:morpholinocarbonyl-His-Ser-Ser-Lys-Leu-Gln-Leu-doxorubicin; D004317:Doxorubicin; D017430:Prostate-Specific Antigen