Antisense therapeutics: lessons from early clinical trials

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Antisense oligodeoxynucleotides represent a novel therapeutic strategy targeting specific gene expression.
• Several oncogene products, including bcl-2, c-raf-1, protein kinase C-alpha, and H-ras, have been identified as potential targets for antisense therapy.

Purpose of the Study:

• To review the early clinical experience with antisense oligodeoxynucleotides in cancer patients.
• To evaluate the toxicity profile, efficacy, and optimal administration of antisense oligodeoxynucleotides.
• To explore the potential of combining antisense therapy with conventional chemotherapy.

Main Methods:

• Review of phase I and II clinical trials involving antisense oligodeoxynucleotides targeting oncogene expression.
• Assessment of target gene (mRNA) downregulation in tumor and surrogate tissues.
• Comparison of continuous infusion versus weekly administration schedules.
• Evaluation of clinical responses and toxicity in cancer patients.

Main Results:

• Antisense oligodeoxynucleotides demonstrated a limited toxicity profile.
• Inhibition of target oncogene expression was observed in tumor tissues, including non-Hodgkin lymphoma.
• Continuous infusion over 2-3 weeks showed advantages in toxicity and target mRNA downregulation compared to weekly administration.
• Antisense therapy alone showed potential in limiting disease progression, but major tumor responses were infrequent.
• Early combination studies with cytotoxic chemotherapy yielded promising results.

Conclusions:

• Antisense oligodeoxynucleotides are generally well-tolerated and can inhibit target gene expression in cancer patients.
• Continuous infusion appears to be a more favorable administration schedule.
• While monotherapy has limitations, the specificity and tolerability of antisense oligodeoxynucleotides support their investigation in combination regimens with chemotherapy.
• Ongoing trials continue to focus on antisense agents targeting bcl-2, c-raf-1, and protein kinase C-alpha.