Antisense therapeutics: lessons from early clinical trials

The authors review the early clinical experience with antisense oligodeoxyn ucleotides, documenting their limited toxicity profile and initial reports of efficacy. Several oncogene products, most notably bcl-2, c-raf-1, protei n kinase C-a, and H-ras, have been evaluated as targets for therapeutic dow nregulation, and oligodeoxynucleotides designed to inhibit the expression o f 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 o f 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 capabl e of limiting disease progression in some patients, but major tumor respons es are uncommon. The specificity and tolerability of these oligodeoxynucleo tides support the investigation of combinations of antisense oligodeoxynucl eotides with cytotoxic chemotherapy, and early combination studies have yie lded results of interest. Antisense oligodeoxynucleotides against bcl-2, c- raf-1, and protein kinase C-a continue to be the focus of ongoing trials. C urr Opin Oncol 2001, 13:499-505 (C) 2001 Lippincott Williams & Wilkins, Inc .