This Article Order Full text via Infotrieve 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 Plenat, F. Articles by Duprez, A. Search for Related Content PubMed PubMed Citation Articles by Plenat, F. Articles by Duprez, A.

American Journal of Pathology, Vol 147, 124-135, Copyright © 1995 by American Society for Investigative Pathology

REGULAR ARTICLES

Cell and tissue distribution of synthetic oligonucleotides in healthy and tumor-bearing nude mice. An autoradiographic, immunohistological, and direct fluorescence microscopy study

F Plenat, N Klein-Monhoven, B Marie, JM Vignaud and A Duprez
Laboratory Pathological Anatomy, Division of Medecine, Vandoeuvre les Nancy, France.

Antisense oligonucleotides have the ability to inhibit individual gene expression in the potential treatment of cancer and viral diseases. However, the way parenterally administered oligonucleotides distribute themselves into healthy tissues or tumors is poorly understood. In this study, the cell and tissue distribution of two modified or unmodified phosphodiester pentadeca-beta-oligonucleotides intravenously administered to healthy or tumor-bearing nude mice was assessed by autoradiography as well as by direct fluorescence and immunoenzymatic histological methods. Resistance of oligonucleotides to degradation by nuclease activity was previously studied in vitro. Using these methods we were able to show the following: 1) within minutes, oligonucleotides permeate all cells and tissues with the exceptions of erythrocytes and intervertebral discs; 2) cell and tissue distribution does not depend on the sequence of the given oligonucleotide; 3) concentration of oligonucleotides is higher within the connective tissue cells than in the interstitial matrix; 4) after uptake, oligomers partition throughout all of the cellular compartments, including at the highest intracellular concentrations in the nuclei; 5) oligonucleotides penetrate easily the tumor cell compartments, oligonucleotide diffusion being unimpeded by the extracellular matrix.

This article has been cited by other articles:

				N. Goebl, B. Berridge, V. J. Wroblewski, and P. L. Brown-Augsburger Development of a Sensitive and Specific in Situ Hybridization Technique for the Cellular Localization of Antisense Oligodeoxynucleotide Drugs in Tissue Sections Toxicol Pathol, June 1, 2007; 35(4): 541 - 548. [Abstract] [Full Text] [PDF]

				S. P. Ho, M. S. Scully, C. M. Krauthauser, E. J. Wexler, M. D. Stow, J. E. Dinchuk, J. S. Kerr, and P. A. Friedman Antisense Oligonucleotides Selectively Regulate Aspartyl beta -Hydroxylase and Its Truncated Protein Isoform in Vitro but Distribute Poorly into A549 Tumors in Vivo J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 795 - 803. [Abstract] [Full Text] [PDF]

				R. M. Crooke, M. J. Graham, M. J. Martin, K. M. Lemonidis, T. Wyrzykiewiecz, and L. L. Cummins Metabolism of Antisense Oligonucleotides in Rat Liver Homogenates J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 140 - 149. [Abstract] [Full Text]

				D. K. Monteith, M. J. Horner, N. A. Gillett, M. Butler, R. Geary, T. Burckin, T. Ushiro-Watanabe, and A. A. Levin Evaluation of the Renal Effects of an Antisense Phosphorothioate Oligodeoxynucleotide in Monkeys Toxicol Pathol, May 1, 1999; 27(3): 307 - 317. [Abstract] [PDF]

				M. J. Graham, S. T. Crooke, D. K. Monteith, S. R. Cooper, K. M. Lemonidis, K. K. Stecker, M. J. Martin, and R. M. Crooke In Vivo Distribution and Metabolism of a Phosphorothioate Oligonucleotide within Rat Liver after Intravenous Administration J. Pharmacol. Exp. Ther., July 1, 1998; 286(1): 447 - 458. [Abstract] [Full Text]

				R. S. Geary, J. M. Leeds, J. Fitchett, T. Burckin, L. Truong, C. Spainhour, M. Creek, and A. A. Levin Pharmacokinetics and Metabolism in Mice of a Phosphorothioate Oligonucleotide Antisense Inhibitor of C-raf-1 Kinase Expression Drug Metab. Dispos., November 1, 1997; 25(11): 1272 - 1281. [Abstract] [Full Text]

				M. Qian, S.-H. Chen, E. Von Hofe, and J. M. Gallo Pharmacokinetics and Tissue Distribution of a DNA-Methyltransferase Antisense (MT-AS) Oligonucleotide and Its Catabolites in Tumor-Bearing Nude Mice J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 663 - 670. [Abstract] [Full Text]

				K. Lappalainen, R. Miettinen, J. Kellokoski, I. Jaaskelainen, and S. Syrjanen Intracellular Distribution of Oligonucleotides Delivered by Cationic Liposomes: Light and Electron Microscopic Study J. Histochem. Cytochem., February 1, 1997; 45(2): 265 - 274. [Abstract] [Full Text] [PDF]