Antisense DNAs as multisite genomic modulators identified by DNA microarray

Antisense oligodeoxynucleotides can selectively block disease-causing genes , and cancer genes have been chosen as potential targets for antisense drug s to treat cancer. However, nonspecific side effects have clouded the true antisense mechanism of action and hampered clinical development of antisens e therapeutics. Using DNA microarrays, we have conducted a systematic chara cterization of gene expression in cells exposed to antisense, either exogen ously or endogenously. Here, we show that in a sequence-specific manner, an tisense targeted to protein kinase A Ria alters expression of the clusters of coordinately expressed genes at a specific stage of cell growth, differe ntiation, and activation. The genes that define the proliferation-transform ation signature are down-regulated, whereas those that define the different iation-reverse transformation signature are up-regulated in antisense-treat ed cancer cells and tumors, but not in host livers, In this differentiation signature, the genes showing the highest induction include genes for the G proteins Rap1 and Cdc42. The expression signature induced by the exogenous ly supplied antisense oligodeoxynucleotide overlaps strikingly with that in duced by endogenous antisense gene overexpression. Defining antisense DNAs on the basis of their effects on global gene expression can lead to identif ication of clinically relevant antisense therapeutics and can identify whic h molecular and cellular events might be important in complex biological pr ocesses, such as cell growth and differentiation.