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Echinomycin: the first bifunctional intercalating agent in clinical trials
Abstract:
Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma, and the P388 leukemia, it was brought into clinical trials by the National Cancer Institute. Recent studies on its cytotoxic action have related its antitumor activity with its ability to bifunctionally intercalate with double stranded DNA. Toxicologic studies were carried out in CDF1 mice and beagle dogs using intravenous injections. For the mice studies the dose ranges were 288-692 mcg/kg (864-2076 mcg/m2) by single bolus, and 112-254 mcg/kg/day (336-762 mcg/m2/day) for five consecutive days. In the dog, dose ranges studied were 8.9-89.4 mcg/kg (178-1788 mcg/m2) by single bolus, and 3.4-33.5 mcg/kg/day (68-670 mcg/m2/day) for five consecutive days. The major toxic effects were found in the gastrointestinal, hepatic, and lymphoreticular systems. These were reversible at all but the highest dose, in dogs that had been treated for five consecutive days. Phase I clinical trials using various intravenous schedules were sponsored by the National Cancer Institute. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. Based on results from these studies, the National Cancer Institute has recently begun phase II trials in a broad range of diseases. These trials will further characterize echinomycin's toxic effects and its antitumor activity.
Insights
Echinomycin, an antibiotic with antitumor properties, showed reversible toxicity in animal studies and early clinical trials. Further Phase II trials are underway to assess its efficacy and safety in various diseases.
Area of Science:
- Pharmacology
- Oncology
- Toxicology
Background:
- Echinomycin is a quinoxaline antibiotic derived from Streptomyces echinatus.
- It exhibits antitumor activity against murine models like B16 melanoma and P388 leukemia.
- Its mechanism involves bifunctional intercalation with double-stranded DNA.
Purpose of the Study:
- To evaluate the toxicologic profile of echinomycin in preclinical animal models (mice and dogs).
- To summarize findings from Phase I clinical trials regarding echinomycin's safety and tolerability.
- To provide a basis for ongoing Phase II clinical trials investigating echinomycin's therapeutic potential.
Main Methods:
- Toxicologic studies involved intravenous administration of echinomycin to CDF1 mice and beagle dogs at various dose ranges and schedules.
- Phase I clinical trials assessed safety and toxicity across different intravenous administration schedules.
- Data analysis focused on identifying major toxic effects and their reversibility.
Main Results:
- Preclinical studies identified gastrointestinal, hepatic, and lymphoreticular systems as primary targets of echinomycin toxicity.
- Toxic effects in dogs were largely reversible, except at the highest dose with prolonged administration.
- Clinical trials reported nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions as common adverse events.
Conclusions:
- Echinomycin demonstrates a toxicity profile primarily affecting the gastrointestinal, hepatic, and lymphoreticular systems.
- Observed toxicities in both animal models and human trials appear manageable and often reversible.
- The National Cancer Institute has initiated Phase II trials to further explore echinomycin's antitumor activity and refine its safety profile in diverse patient populations.