title: Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans.
abstract: OBJECTIVE
  The overexpression of c-myc associated with uncontrolled cell proliferation is a frequent genetic event in androgen-refractory prostatic neoplasia. The purpose of this study was to evaluate the bioavailability and efficacy of a novel antisense phosphorodiamidate morpholino oligomer directed against c-myc, AVI-4126, in PC-3 androgen-independent human prostate cancer xenograft murine model and its safety in a Phase I human clinical study.
  
  
  METHODS
  AVI-4126 administration in athymic mice bearing s.c. PC-3 xenografts was carried out to determine the bioavailability, tolerance, antitumor activity, and histological changes induced by targeted inhibition of c-Myc expression using a specific morpholine antisense oligomer. The Phase I safety study involved a single center, open label, dose-escalating design in healthy volunteers after i.v. administration of AVI-4126.
  
  
  RESULTS
  The data reveal that AVI-4126 targets and inhibits c-myc translation in a sequence-specific manner and causes significant growth inhibition and apoptosis in prostate cancer cells and in s.c. tumor xenografts. A 75-80% reduction in tumor burden was observed in AVI-4126-treated animals compared with the scrambled oligomer and saline control groups. Histologically, tumors grown in the athymic mice treated with AVI-4126 were less cellular and vascular than those in control mice and showed an increased level of cellular degeneration, cytoplasmic vacuoles, and hyperchromatic nuclei. Phase I safety trials in humans via i.v. route of administration showed no toxicity or serious adverse events.
  
  
  CONCLUSIONS
  The present study demonstrates that inhibition of c-Myc expression by antisense phosphorodiamidate morpholino oligomer is a promising new and safe therapeutic strategy for prostate cancer.
authors.affiliation: AVI BioPharma Inc., Corvallis, Oregon 97333, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.forename: Vikram
authors.initials: V
authors.lastname: Arora
authors.forename: A J
authors.initials: AJ
authors.lastname: Acker
authors.forename: David H
authors.initials: DH
authors.lastname: Mason
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D015536:Down-Regulation; D016259:Genes, myc; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008858:Microscopy, Phase-Contrast; D009025:Morpholines / Q000627:therapeutic use*; D060172:Morpholinos; D009336:Necrosis; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014176:Protein Biosynthesis; D013997:Time Factors
chemical_list: D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense