© 2003 by Oxford University Press
© 2003 Oxford University Press
ARTICLE |
Effects of MYCN Antisense Oligonucleotide Administration on Tumorigenesis in a Murine Model of Neuroblastoma
Affiliations of authors: C. A. Burkhart, A. J. Cheng, J. Madafiglio, M. Kavallaris, M. Mili, G. M. Marshall, M. D. Norris, M. Haber, Children’s Cancer Institute Australia for Medical Research, Sydney, Australia; W. A. Weiss, University of California at San Francisco, San Francisco; L. M. Khachigian, Centre for Thrombosis and Vascular Research, University of New South Wales, Sydney.
Correspondence to: Michelle Haber, PhD, Children’s Cancer Institute Australia for Medical Research, High St., P.O. Box 81, Randwick, NSW, Australia 2031 (e-mail: m.haber{at}unsw.edu.au).
Background: Human MYCN (hMYCN) oncogene amplification is a powerful predictor of treatment failure in childhood neuroblastoma, and dysregulation of hMYCN protein expression appears to be critically involved in the pathogenesis of this disease. We used hMYCN antisense (AS) oligonucleotides to investigate, both in vitro and in vivo, the therapeutic potential of inhibiting hMYCN expression. Methods: We transiently transfected human neuroblastoma IMR-32 cells, which have an amplified hMYCN gene, with fluorescently labeled hMYCN AS or scrambled (SCR) control oligonucleotides and used fluorescence-activated cell sorting to enrich for cell populations containing different levels of the oligonucleotides. We used fluorescence immunocytochemistry or reverse transcription polymerase chain reaction to assay gene expression levels and trypan blue exclusion to assay growth inhibition in the cell populations. We examined the effects of continuous treatment for 6 weeks with AS or SCR oligonucleotides via subcutaneously implanted microosmotic pumps on tumor growth in a transgenic mouse model of hMYCN-induced neuroblastoma (n = 20 mice per group). All statistical tests were two-sided. Results: IMR-32 cells treated with AS oligonucleotides had approximately half as much hMYCN protein and cell proliferation as either SCR oligonucleotide–transfected or mock-transfected controls; the differences were statistically significant. Transgenic mice treated with AS oligonucleotides had lower tumor incidence and statistically significantly lower tumor mass than SCR-treated or untreated control mice. Compared with control treatments, AS oligonucleotide treatment in vitro and in vivo was associated with decreased expression of hMYCN and putative hMYCN target genes but not with that of closely related genes. Several AS oligonucleotide–treated mice developed tumors contralateral to the site of oligonucleotide administration, whereas SCR oligonucleotide–treated or untreated mice displayed bilateral tumor growth. Conclusions: Decreased expression of hMYCN protein is achievable with the use of AS oligonucleotide treatment, even in the presence of hMYCN oncogene amplification. Antisense strategies targeting the hMYCN oncogene in vivo decrease mouse neuroblastoma tumorigenesis. Investigation of their clinical effect in children with neuroblastoma is warranted.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. D. Hogarty, M. D. Norris, K. Davis, X. Liu, N. F. Evageliou, C. S. Hayes, B. Pawel, R. Guo, H. Zhao, E. Sekyere, et al. ODC1 Is a Critical Determinant of MYCN Oncogenesis and a Therapeutic Target in Neuroblastoma Cancer Res., December 1, 2008; 68(23): 9735 - 9745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Chesler, C. Schlieve, D. D. Goldenberg, A. Kenney, G. Kim, A. McMillan, K. K. Matthay, D. Rowitch, and W. A. Weiss Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in Neuroblastoma Cancer Res., August 15, 2006; 66(16): 8139 - 8146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Haber, J. Smith, S. B. Bordow, C. Flemming, S. L. Cohn, W. B. London, G. M. Marshall, and M. D. Norris Association of High-Level MRP1 Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma J. Clin. Oncol., April 1, 2006; 24(10): 1546 - 1553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Giannini, F. Cerignoli, M. Mellone, I. Massimi, C. Ambrosi, C. Rinaldi, C. Dominici, L. Frati, I. Screpanti, and A. Gulino High Mobility Group A1 Is a Molecular Target for MYCN in Human Neuroblastoma Cancer Res., September 15, 2005; 65(18): 8308 - 8316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Norris, J. Smith, K. Tanabe, P. Tobin, C. Flemming, G. L. Scheffer, P. Wielinga, S. L. Cohn, W. B. London, G. M. Marshall, et al. Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro Mol. Cancer Ther., April 1, 2005; 4(4): 547 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Hansford, W. D. Thomas, J. M. Keating, C. A. Burkhart, A. E. Peaston, M. D. Norris, M. Haber, P. J. Armati, W. A. Weiss, and G. M. Marshall Mechanisms of embryonal tumor initiation: Distinct roles for MycN expression and MYCN amplification PNAS, August 24, 2004; 101(34): 12664 - 12669. [Abstract] [Full Text] [PDF]
|
|