Dong-Mei Feng

A peptide–doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen in vivo

We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However, L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377,202. This improvement in therapeutic index correlated with the selective localization of leucine–doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to L-377,202.

Design and Synthesis of a Selective PSA Cleavable Peptide-Doxorubicin Prodrug Which Targets PSA Positive Tumor Cells

Prostate cancer is the second leading cause of cancer mortality in males. It is estimated that 37,000 men died of prostate carcinoma in the United States in 1999 [1]. While cancer that is confined to the prostate can be treated with surgery or radiation, the prognosis for metastatic disease is poor.