title: Characterization of a novel prostate-specific antigen-activated peptide-doxorubicin conjugate in patients with prostate cancer.
abstract: OBJECTIVE
  To evaluate safety and pharmacokinetics (PK), and determine the recommended dose for efficacy studies, of L-377202, a novel peptide conjugate of doxorubicin (Dox) that releases the active metabolites leucine-doxorubicin (Leu-Dox) and Dox on cleavage by membrane-bound prostate-specific antigen (PSA).
  
  
  METHODS
  Nineteen patients with advanced hormone-refractory prostate cancer were treated intravenously with 71 cycles of L-377202 at escalating dose levels of 20 (n = 1), 40 (n = 3), 80 (n = 4), 160 (n = 3), 225 (n = 6), and 315 mg/m(2) (n = 2) once every 3 weeks. Toxicity, response, and PK of L-377202 were assessed.
  
  
  RESULTS
  L-377202 was well tolerated. Dose-limiting grade 4 neutropenia was noted in two of two patients administered 315 mg/m(2) (both patients were able to resume therapy at 225 mg/m(2)). The recommended dose for efficacy studies was 225 mg/m(2), which induced grade 4 neutropenia in one of six patients. PK studies demonstrated that L-377202 was metabolized to Leu-Dox and Dox. PK were linear; after administration of single doses of 225 mg/m(2), the mean area under the concentration-time profiles of L-377202, Leu-Dox, and Dox were 6 micromol x L/h, 4 micromol x L/h, and 1 micromol x L/h, and peak concentrations were 14 micromol/L, 5 micromol/L, and 120 nmol/L, respectively. At 225 and 315 mg/m(2), five patients completed at least three cycles of therapy; two patients had a greater than 75% decrease in PSA, and one patient had a stabilized PSA. No response was noted at dose levels less than 225 mg/m(2).
  
  
  CONCLUSIONS
  This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick 08901, USA. dipaolrs@umdnj.edu
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: John
authors.initials: J
authors.lastname: Rinehart
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: Scott
authors.initials: S
authors.lastname: Ebbinghaus
authors.forename: Eric
authors.initials: E
authors.lastname: Rubin
authors.forename: Terry
authors.initials: T
authors.lastname: Capanna
authors.forename: Marie
authors.initials: M
authors.lastname: Ciardella
authors.forename: Susan
authors.initials: S
authors.lastname: Doyle-Lindrud
authors.forename: Susan
authors.initials: S
authors.lastname: Goodwin
authors.forename: Michelle
authors.initials: M
authors.lastname: Fontaine
authors.forename: Ned
authors.initials: N
authors.lastname: Adams
authors.forename: Adrienne
authors.initials: A
authors.lastname: Williams
authors.forename: Michael
authors.initials: M
authors.lastname: Schwartz
authors.forename: Greg
authors.initials: G
authors.lastname: Winchell
authors.forename: Karen
authors.initials: K
authors.lastname: Wickersham
authors.forename: Paul
authors.initials: P
authors.lastname: Deutsch
authors.forename: Siu-Long
authors.initials: SL
authors.lastname: Yao
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C416722:L 377202; D009842:Oligopeptides; D011355:Prodrugs; D004317:Doxorubicin; D017430:Prostate-Specific Antigen