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Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine
R R Love1, P P Carbone, A K Verma
1University of Wisconsin Comprehensive Cancer Center, Madison.
Background:
alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice.
Purpose:
A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG]).
Methods:
Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels.
Results:
In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour.
Conclusions:
These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day.
Implications:
Studies investigating prevention of cancers with DFMO are under consideration.
Insights
Alpha-difluoromethylornithine (DFMO) at 0.5 g/m2 daily effectively inhibits ornithine decarboxylase (ODC) in humans with minimal toxicity. This supports further research into DFMO for cancer chemoprevention.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Alpha-difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase (ODC), crucial for polyamine synthesis.
- Elevated ODC levels correlate with tumor promotion; ODC inhibition shows promise in suppressing tumor development.
Purpose of the Study:
- To determine the lowest oral dose of DFMO for achieving at least 50% ODC inhibition in human skin.
- To assess DFMO's clinical toxicity at various doses, aiming for grade 1 or lower (ECOG).
Main Methods:
- A randomized phase I study involving cancer patients and cancer-free subjects at risk.
- DFMO administered orally at doses ranging from 0.125 to 1.0 g/m2 daily or divided.
- Evaluation of ODC activity via skin biopsy specimens and assessment of adverse events.
Main Results:
- A daily dose of 0.5 g/m2 DFMO demonstrated significant ODC inhibition (≥50%) in subjects with normal pretreatment levels.
- This dose (0.5 g/m2 daily) was identified as having minimal clinical toxicity.
- DFMO exhibited linear pharmacokinetics, with a half-life of 3.5 hours at the effective dose.
Conclusions:
- The findings support the use of 0.5 g/m2 of DFMO daily in phase II chemoprevention studies.
- Further investigations into DFMO for cancer prevention are warranted and under consideration.