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

Abstract

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.

• Authors: Patrick L Iversen, Vikram Arora, A J Acker, David H Mason, Gayathri R Devi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 7 Pg. 2510-9 (Jul 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12855625 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Morpholines
• Morpholinos
• Oligonucleotides, Antisense

Topics

• Animals
• Apoptosis
• Cell Division
• Cell Line, Tumor
• Cell Survival
• Chromatography, High Pressure Liquid
• Down-Regulation
• Genes, myc
• Humans
• Male
• Mice
• Mice, Nude
• Microscopy, Phase-Contrast
• Morpholines (therapeutic use)
• Morpholinos
• Necrosis
• Neoplasm Transplantation
• Oligonucleotides, Antisense (therapeutic use)
• Prostatic Neoplasms (drug therapy)
• Protein Biosynthesis
• Time Factors