Prospects for the therapeutic use of antisense oligonucleotides in malignant lymphomas

Abstract

Combinations of cytotoxic drugs, based almost entirely upon the results of empirical clinical trials, are the foundation of the modern management of the non-Hodgkin's lymphomas. While highly effective in the high-grade (particularly pediatric) lymphomas, and able to cure a significant fraction of intermediate-grade lymphomas, it has yet to be proven that patients with low-grade lymphomas can be cured by chemotherapy. Yet even if 100% of patients were potentially curable by chemotherapy, the significant medical cost with respect to both immediate and late toxicity is reason enough to search for radically different approaches to therapy. Of particular appeal is the possibility that therapy might be developed that is targeted to the very genetic lesions that are responsible for the pathogenesis of lymphomas. Such therapy should, by definition, be largely specific for the lymphoma cells, and hence devoid of the major side effects presently encountered. Recent advances in the understanding of the molecular basis of lymphomagenesis have provided sufficient information to begin to develop approaches of this kind. Here, I discuss the prospects for sequence-specific therapy, focusing specifically on antisense oligonucleotides. These short stretches of DNA bind specifically to RNA molecules and prevent their translation. If the targeted RNA molecules are specific to the tumor cells, or derived from pathogenetically relevant viral genomes, such therapy has at least the theoretical possibility of inhibiting tumor cell growth, or even killing tumor cells, without causing significant damage to normal cells.