Dose De-escalation Chemoprevention Trial of  -Difluoromethylornithine in Patients With Colon Polyps

Abstract

If DFMO is also found to be effective in suppressing polyamine contents in other target tissues, it may be useful in preventing a wide range of human epithelial cancers, including those of the prostate and breast.

The Effect of Difluoromethylornithine on Decreasing Prostate Size and Polyamines in Men: Results of a Year-Long Phase IIb Randomized Placebo-Controlled Chemoprevention Trial

“…Three to six cores of snap-frozen prostate tissues were used for the polyamine analysis. Technical aspects have been reported previously (25)(26)(27)(28)(29)(30); briefly, this included standard polyamine preparations and use of internal standards. Prostate tissue was minced in 300 AL of 9.2 N perchloric acid, homogenized vigorously with the resulting lysate stored overnight at 4jC, and rehomogenized.…”

Polyamines and cancer: old molecules, new understanding

“…For example, a limiting dose of DFMO does lower polyamine levels substantially in cervical tissue, but does not do so in oral or breast tissue, and probably the bladder 9,[71][72][73][74][75][76][77] . In many tissues, including the colonic mucosa, DFMO suppresses putrescine and spermidine, but not spermine 66,78 . In prostate tissue, which contains 5-10 times more spermine than either putrescine or spermidine, a one-month treatment with DFMO did reduce spermine levels 76 .…”

“…In the various human epithelial tissues studied, the dose of DFMO that was effective in lowering polyamine levels or inhibiting ODC ranged from about 0.25-1.0 g/m 2 /day 73,76,78 . As the dose of DFMO that produces noticeable hearing changes is about 1.0 g/m 2 /day, lower doses might be both efficacious and safe.…”

American Society of Preventive Oncology Distinguished Career Achievement Lecture 2006—Enjoy the Journey: The Long and Winding Road of Chemoprevention Agent Development

“…These observations led to a series of clinical chemoprevention studies in concert with my Arizona colleague Gene Gerner (25)(26)(27). For all these trials, patients who had had a prior colonic adenoma were our target population.…”

“…The basic strategy was this: because we knew the highest dose at which the drug would be given in a therapeutic trial, we implemented a dose de-escalation design. In the initial 1-month trial, the goal was to achieve a dose that no longer modulated polyamines in rectal colonic mucosa (25). Based on these results, a 1-year trial using three doses of difluoromethylornithine and a placebo group was conducted in which the goal was to show polyamine modulation and no toxicity.…”