Antisense therapeutics: lessons from early clinical trials

The authors review the early clinical experience with antisense oligodeoxynucleotides, documenting their limited toxicity profile and initial reports of efficacy. Several oncogene products, most notably bcl-2, c-raf-1, protein kinase C-alpha, and H-ras, have been evaluated as targets for therapeutic downregulation, and oligodeoxynucleotides designed to inhibit the expression of these products specifically have been studied extensively in phase I and II trials in cancer patients. Inhibition of target expression in tumor (non-Hodgkin lymphoma) and surrogate tissues has been demonstrated in several of these trials. Continuous infusion over 2 to 3 weeks appears preferable to weekly administration for toxicity and downregulation of target mRNA. The efficacy data available suggest that antisense therapy alone appears capable of limiting disease progression in some patients, but major tumor responses are uncommon. The specificity and tolerability of these oligodeoxynucleotides support the investigation of combinations of antisense oligodeoxynucleotides with cytotoxic chemotherapy, and early combination studies have yielded results of interest. Antisense oligodeoxynucleotides against bcl-2, c-raf-1, and protein kinase C-alpha continue to be the focus of ongoing trials.