title: In vivo tumor growth inhibition and biodistribution studies of locked nucleic acid (LNA) antisense oligonucleotides.
abstract: Locked nucleic acids (LNA) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. The LNA oligonucleotides (LNA PO ODNs) are very stable in vitro and in vivo without the need for a phosphorothiolated backbone. In this study we tested the biological fate and the efficacy in tumor growth inhibition of antisense oligonucleotides directed against the gene of the large subunit of RNA polymerase II (POLR2A) that are completely synthesized as LNA containing diester backbones. These full LNA oligonucleotides strongly reduce POLR2A protein levels. Full LNA PO ODNs appeared to be very stable compounds when injected into the circulation of mice. Full LNA PO ODNs were continuously administered for 14 days to tumor-bearing nude mice. Tumor growth was inhibited sequence specifically at dosages from 1 mg/kg/day. LNA PO ODNs appeared to be non-toxic at dosages <5 mg/kg/day. Biodistribution studies showed the kidneys to have the highest uptake of LNA PO ODNs and urinary secretion as the major route of clearance. This report shows that LNA PO ODNs are potent genotype-specific drugs that can inhibit tumor growth in vivo.
authors.affiliation: Department of Neurogenetics, Academical Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Fluiter
authors.forename: Anneloor L M A
authors.initials: AL
authors.lastname: ten Asbroek
authors.forename: Marit B
authors.initials: MB
authors.lastname: de Wissel
authors.forename: Marja E
authors.initials: ME
authors.lastname: Jakobs
authors.forename: Margit
authors.initials: M
authors.lastname: Wissenbach
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.forename: Otto
authors.initials: O
authors.lastname: Olsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Oerum
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012319:RNA Polymerase II / Q000032:analysis / Q000235:genetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D016376:Oligonucleotides, Antisense; D012319:RNA Polymerase II