Antisense strategies in the treatment of leukemias.

Oligodeoxynucleotides are short nucleotide sequences of DNA synthesized as reverse complements of the desired mRNA target's nucleotide sequence. On formation of the RNA-DNA duplex, gene expression is prevented. Delivery of oligodeoxynucleotides targeting oncogene-encoded mRNAs to human cells in culture is associated with inhibition of cell proliferation and, in some circumstances, cell death. Oligodeoxynucleotides chemically modified to survive nuclease attack have been used systemically in murine models of human hematologic malignancies. In some studies, a measurable antileukemia effect has been observed. On the basis of these preclinical investigations, phase 1 clinical trials involving ex vivo and systemic administration of such compounds are now in progress at different institutions. Despite the remarkable progress of the past few years, much remains to be addressed on uptake, cellular distribution, mechanism(s) of action, and metabolism of such compounds. Furthermore, the "antisense effects" of the oligodeoxynucleotides might also be associated with nonspecific effects. In conclusion, time, a great deal of effort, and patience will tell whether such compounds will have a role as novel antileukemia therapeutic agents.