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 pro state-specific antigen. In the presence of prostate tumor cells secreting p rostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorub icin, 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 t imes more effective than was conventional doxorubicin at inhibiting the gro wth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostat e tumor cells secreting prostate-specific antigen showed considerable reduc tions in tumor burden with minimal total body weight loss when treated with L-377,202. This improvement in therapeutic index correlated with the selec tive localization of leucine-doxorubicin and free doxorubicin in tissues se creting prostate-specific antigen after exposure to L-377,202.