This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Z. Articles by Zhang, R. Search for Related Content PubMed PubMed Citation Articles by Zhang, Z. Articles by Zhang, R.

Radiosensitization by Antisense Anti-MDM2 Mixed-Backbone Oligonucleotide in in Vitro and in Vivo Human Cancer Models

¹ Department of Pharmacology and Toxicology,² Division of Clinical Pharmacology,³ Department of Radiation Oncology,⁴ Comprehensive Cancer Center, and⁵ Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama, and⁶ Hybridon, Inc., Cambridge, Massachusetts

ABSTRACT

Purpose: The MDM2 oncogene, amplified or overexpressed in many human cancers, has been suggested to be a novel target for cancer therapy. We have demonstrated a second-generation antisense antihuman-MDM2 oligonucleotide to have antitumor activity when administered alone or in combination with cancer chemotherapeutic agents. In the present study, we investigated the effect of the antisense oligonucleotide on radiation therapy.

Experimental Design: The in vitro radiosensitization activity was determined in cell lines of human cancers of prostate (LNCaP and PC3), breast (MCF-7 and MDA-MB-468), pancreas (PANC-1), and glioma (U87-MG and A172) and its in vivo radiosensitization activity in xenograft models of LNCaP, PC3, MCF-7, MDA-MB-468, and PANC-1.

Results: In cells containing at least one functional p53 allele (LNCaP, U87-MG, and A172), after specific inhibition of MDM2 expression, p53 and p21 levels were elevated. In LNCaP cells, the Bax level was increased, and Bcl-2 and E2F1 levels were decreased. In PC3 cells that are p53 null, after inhibition of MDM2 expression, Bax and p21 levels were elevated, and E2F1 levels were decreased. On the basis of in vitro clonogenic assay, the antisense oligonucleotide, in a sequence-specific manner, significantly increased radiation-induced antiproliferation effects. It also increased radiation-induced inhibitory effects on tumor growth in SCID or nude mice bearing LNCaP, PC3, MCF-7, MDA-MB-468, and PANC-1 xenografts.

Conclusions: These results suggest that MDM2 has a role in radiation therapy of human cancers, regardless of p53 status, providing a basis for future development of MDM2 inhibitors, such as antisense oligonucleotides, as radiosensitizers.

This article has been cited by other articles:

				S. Supiot, R. P. Hill, and R. G. Bristow Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53 Mol. Cancer Ther., April 1, 2008; 7(4): 993 - 999. [Abstract] [Full Text] [PDF]

				M. Li, Z. Zhang, D. L. Hill, H. Wang, and R. Zhang Curcumin, a Dietary Component, Has Anticancer, Chemosensitization, and Radiosensitization Effects by Down-regulating the MDM2 Oncogene through the PI3K/mTOR/ETS2 Pathway Cancer Res., March 1, 2007; 67(5): 1988 - 1996. [Abstract] [Full Text] [PDF]

				M. Lacroix, R.-A. Toillon, and G. Leclercq p53 and breast cancer, an update. Endocr. Relat. Cancer, June 1, 2006; 13(2): 293 - 325. [Abstract] [Full Text] [PDF]

				H. K. Koblish, S. Zhao, C. F. Franks, R. R. Donatelli, R. M. Tominovich, L. V. LaFrance, K. A. Leonard, J. M. Gushue, D. J. Parks, R. R. Calvo, et al. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo Mol. Cancer Ther., January 1, 2006; 5(1): 160 - 169. [Abstract] [Full Text] [PDF]

				Z. ZHANG, H. WANG, M. LI, E. RAYBURN, S. AGRAWAL, and R. ZHANG Novel MDM2 p53-Independent Functions Identified through RNA Silencing Technologies Ann. N.Y. Acad. Sci., November 1, 2005; 1058(1): 205 - 214. [Abstract] [Full Text] [PDF]

				R. Bianco, R. Caputo, R. Caputo, V. Damiano, S. De Placido, C. Ficorella, S. Agrawal, A. R. Bianco, F. Ciardiello, and G. Tortora Combined Targeting of Epidermal Growth Factor Receptor and MDM2 by Gefitinib and Antisense MDM2 Cooperatively Inhibit Hormone-Independent Prostate Cancer Clin. Cancer Res., July 15, 2004; 10(14): 4858 - 4864. [Abstract] [Full Text] [PDF]