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Nucleic Acids Research 2004 32(22):6585-6594; doi:10.1093/nar/gkh997
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Published online 16 December 2004

Nucleic Acids Research, Vol. 32 No. 22 © Oxford University Press 2004; all rights reserved

Sequence-dependent cytotoxicity of second-generation oligonucleotides

Denis Drygin, Stephen Barone and C. Frank Bennett*

Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, CA 92008, USA

* To whom correspondence should be addressed. Tel: +1 760 603 2336; Fax: +1 760 603 4652; Email: fbennett{at}isisph.com

Received as resubmission October 4, 2004; Revised and Accepted November 24, 2004

In this study, we have examined the potential of second-generation antisense chimeric 2'-O-(2-methoxy)ethyl/DNA phosphorothioate oligonucleotides (ONs) to affect cell growth through non-antisense mechanisms. Evaluation of a series of ONs demonstrated that only a small number were cytotoxic at concentrations close to those required for antisense activity. Toxicity of the ONs appeared to be sequence dependent and could be affected by base and backbone modifications. Caspase-3 activation occurs with some ONs and it is most likely secondary to necrosis rather than apoptosis, since cells treated with toxic ONs did not show chromatin condensation, but did exhibit high-extracellular lactate dehydrogenase activity. Caspase-3 activation does not correlate with and appears not to be required for the inhibition of cell proliferation. Toxicity was only observed when ONs were delivered intracellularly. The mechanism by which one of the most cytotoxic ON produces cytotoxicity was investigated in more detail. Treatment with the cytotoxic ON caused disruption of lysosomes and Pepstatin A, a specific inhibitor of aspartic proteases, reduced the cytotoxicity of the ON. Reduction of lysosomal aspartic protease cathepsin D by prior treatment with cathepsin D-specific antisense ON did not attenuate the cytotoxicity, suggesting that other aspartic proteases play a crucial role in the cellular proliferation inhibition by ONs.


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