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Phase I evaluation of intravenous difluoromethylornithine--a polyamine inhibitor
Abstract:
Difluoromethylornithine (DFMO), a non-competitive inhibitor of ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine synthetic pathway was evaluated in a Phase I trial. Intravenous DFMO was given to twenty patients with refractory leukemia by continuous infusion in doses from 5.5 to 64 g/m2. Toxicity clearly attributable to the drug was not severe and other than nausea and vomiting did not increase with dose. The previously reported ototoxicity which occurred with the oral form appeared to be less frequent. Loss of hearing which improved when the drug was stopped was seen in four patients, three of whom were simultaneously receiving aminoglycosides. Anorexia occurred in some patients at all doses. Vomiting, necessitating dosage reduction, was a significant problem at the highest dose administered. No patient achieved a remission but there was stabilization or decrease in circulating blast cells in several patients. This growth inhibition did not appear to be dosage related.
Insights
Difluoromethylornithine (DFMO) showed limited efficacy in refractory leukemia patients during a Phase I trial. While generally well-tolerated, vomiting and anorexia were noted, with some hearing loss observed.
Area of Science:
- Oncology
- Pharmacology
Background:
- Polyamines are crucial for cell growth and proliferation.
- Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine synthesis.
- Difluoromethylornithine (DFMO) inhibits ODC, impacting polyamine production.
Purpose of the Study:
- To evaluate the safety and tolerability of intravenous DFMO in patients with refractory leukemia.
- To assess the preliminary efficacy of DFMO in this patient population.
Main Methods:
- A Phase I clinical trial was conducted.
- Twenty patients with refractory leukemia received intravenous DFMO via continuous infusion.
- Doses ranged from 5.5 to 64 g/m2.
Main Results:
- DFMO was generally well-tolerated, with toxicity not significantly increasing with dose, excluding nausea and vomiting.
- Ototoxicity, previously noted with oral DFMO, appeared less frequent.
- Nausea, vomiting, and anorexia were observed side effects.
- Vomiting necessitated dose reduction at the highest dose.
- No complete remissions were achieved, but stabilization or decrease in circulating blast cells occurred in several patients.
- Growth inhibition did not appear to be dose-dependent.
Conclusions:
- Intravenous DFMO demonstrated a manageable toxicity profile in refractory leukemia patients.
- While not curative, DFMO showed some potential for disease stabilization.
- Further investigation into DFMO's role in leukemia treatment may be warranted, considering its side effect profile.