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Clin Cancer Res. 2003 Jul;9(7):2510-9.

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

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1
AVI BioPharma Inc., Corvallis, Oregon 97333, USA.

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.

PMID:
12855625
[Indexed for MEDLINE]
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