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Antisense therapeutics: lessons from early clinical trials
K T Flaherty1, J P Stevenson, P J O'Dwyer
1University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA. ktflaherty@aol.com
Current Opinion in Oncology
|October 24, 2001
Summary
Antisense oligodeoxynucleotides show limited toxicity and some efficacy in early cancer trials. Continuous infusion may improve outcomes, supporting combination therapies for better patient responses.
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.
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