Publications [#99268] of Gayathri R Devi

Papers Published

1. PL Iversen, V Arora, AJ Acker, DH Mason, GR Devi, Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans., Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 9 no. 7 (July, 2003), pp. 2510-9, ISSN 1078-0432
   (last updated on 2013/05/16)

   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.

   Keywords:
   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 • Morpholinos • Necrosis • Neoplasm Transplantation • Oligonucleotides, Antisense • Prostatic Neoplasms • Protein Biosynthesis • Time Factors • drug therapy* • therapeutic use*