BACKGROUND: Differential mRNA splicing and alternative promoter usage of the 
TP73 gene results in the expression of multiple NH2-truncated isoforms that act 
as oncogenes. Abundant levels of these p73 variants in a variety of human 
cancers correlated with adverse clinical prognosis and response failure to 
conventional therapies, underscoring their relevance as marker for disease 
severity and target for cancer intervention. With respect to an equally 
important role for amino-truncated p73 splice forms (DeltaTAp73) and DeltaNp73 
(summarized as DNp73) in the tumorigenic process, we designed locked nucleic 
acid (LNA) antisense oligonucleotide (ASO) gapmers against individual species 
that were complementary to DeltaEx2 and DeltaEx2/3 splice junctions and a region 
in exon 3B unique for DeltaN' and DeltaN.
RESULTS: Treatment of cancer cells with these ASOs resulted in a strong and 
specific reduction of tumorigenic p73 transcripts and proteins, importantly, 
without abolishing the wild-type p73 tumor suppressor form as observed with 
p73-shRNA. The specific antisense oligonucleotides rescued cells from apoptosis 
inhibition due to overexpression of their corresponding amino-truncated p73 
isoform and decreased tumor cell proliferation. Furthermore, ASO-116 against 
DeltaEx2/3 coupled to magnetic nanobead polyethyleneimine (MNB/PEI) carriers 
significantly inhibited malignant melanoma growth, which correlated with a shift 
in the balance between endogenous TAp73 and DeltaEx2/3 towards apoptotic 
full-length p73.
CONCLUSION: Our study demonstrates the successful development of LNA-ASOs that 
selectively differentiate between the closely related p73 oncoproteins, and 
provide new tools to further delineate their biological properties in different 
human malignancies and for therapeutic cancer targeting.