title: A peptide-doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen in vivo.
abstract: 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.
authors.affiliation: Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: D
authors.initials: D
authors.lastname: DeFeo-Jones
authors.forename: V M
authors.initials: VM
authors.lastname: Garsky
authors.forename: B K
authors.initials: BK
authors.lastname: Wong
authors.forename: D M
authors.initials: DM
authors.lastname: Feng
authors.forename: T
authors.initials: T
authors.lastname: Bolyar
authors.forename: K
authors.initials: K
authors.lastname: Haskell
authors.forename: D M
authors.initials: DM
authors.lastname: Kiefer
authors.forename: K
authors.initials: K
authors.lastname: Leander
authors.forename: E
authors.initials: E
authors.lastname: McAvoy
authors.forename: P
authors.initials: P
authors.lastname: Lumma
authors.forename: J
authors.initials: J
authors.lastname: Wai
authors.forename: E T
authors.initials: ET
authors.lastname: Senderak
authors.forename: S L
authors.initials: SL
authors.lastname: Motzel
authors.forename: K
authors.initials: K
authors.lastname: Keenan
authors.forename: M
authors.initials: M
authors.lastname: Van Zwieten
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: R
authors.initials: R
authors.lastname: Freidinger
authors.forename: J
authors.initials: J
authors.lastname: Huff
authors.forename: A
authors.initials: A
authors.lastname: Oliff
authors.forename: R E
authors.initials: RE
authors.lastname: Jones
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000097:blood / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C416722:L 377202; D009842:Oligopeptides; D011355:Prodrugs; D004317:Doxorubicin; D017430:Prostate-Specific Antigen