Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans.

Published

Journal Article

PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

Full Text

Duke Authors

Cited Authors

  • Iversen, PL; Arora, V; Acker, AJ; Mason, DH; Devi, GR

Published Date

  • July 2003

Published In

Volume / Issue

  • 9 / 7

Start / End Page

  • 2510 - 2519

PubMed ID

  • 12855625

Pubmed Central ID

  • 12855625

International Standard Serial Number (ISSN)

  • 1078-0432

Language

  • eng

Conference Location

  • United States