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The potency of siRNA-mediated growth inhibition following silencing of essential genes is dependent on siRNA design and varies with target sequence.

Silencing genes essential for replication and division using siRNA has potential as a therapeutic strategy for cancer treatment. In order to identify the most potent siRNA, target sequence and siRNA design must be considered together, as tolerance for structural changes can be sequence-dependent. Here we have used growth inhibition assays to investigate the effects of silencing of RRM1, RRM2, and PLK1 with standard siRNAs, Stealth() duplexes, and Dicer substrate siRNAs. The growth inhibitory effect of RRM1, RRM2, or PLK1 knockdown in A549 cells varied with mRNA target site and the format of the siRNA, with longer modified siRNAs generally more effective than standard siRNAs specific for the same target site. Standard siRNAs of varying activity became more potent inhibitors of growth when converted to Stealth() duplexes, and the increase in activity was due to a combination of chemical modification and length. In each case, the effect on activity of changing the siRNA format depended on the siRNA sequence. Taken together these results suggest that, in vitro, longer siRNAs with chemical modifications are in general more active than standard siRNAs targeting the same site, and that structure, chemical modification, and target site must be considered together to identify the most active siRNAs.