Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps.
BACKGROUND
alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models. In these animal models, DFMO has been especially active in preventing carcinogen-induced epithelial cancers, including those of the skin, colon, breast, and urinary bladder. Although DFMO is known to exert its diverse biological effects by suppressing intracellular pools of the polyamines putrescine and spermidine, the precise mechanism by which polyamine depletion, induced by DFMO, suppresses carcinogenesis is unknown.


OBJECTIVE
The specific aim of our study was to determine the lowest dose of DFMO that would deplete target tissue (colorectal mucosa) levels of these polyamines in humans who had undergone prior removal of colon polyps while producing minimal toxic effects.


METHODS
A dose de-escalation chemoprevention trial of DFMO was conducted in 111 patients (36 female and 75 male) who were in generally good health, aged 39-79, and who had undergone colonoscopy for surgical removal of an adenomatous colon polyp greater than 3 mm within 5 years prior to entering the study. Groups of patients (12-20 patients per group) were orally treated with single, daily doses of DFMO ranging from 3.0 to 0.1 g/m2 for 4 weeks (28 days). Prior to initiation of DFMO treatment and at the end of treatment, six colorectal biopsy specimens were collected from each patient, along with serum samples. All biopsies were performed between 9 AM and noon to avoid possible effects of diurnal variations in laboratory end points. Samples for analysis of plasma DFMO levels were also collected during this time period on the day after the last day of drug administration.


RESULTS
DFMO caused a decrease in both putrescine content and the ratio of spermidine to spermine for all dose groups down to 0.25 g/m2. Both putrescine content and the ratio of spermidine to spermine and changes in these parameters as a function of DFMO treatment decreased as a function of donor age. None of the 30 patients receiving either 0.25 or 0.5 g/m2 experienced any clinical ototoxicity in this trial.


CONCLUSIONS
DFMO is both safe and effective in reducing colorectal mucosal polyamine contents when it is administered orally to patients at doses as low as 0.25 g/m2 for 28 days. No ototoxicity was observed at doses up to twice this amount.


CONCLUSIONS
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.
Department of Medicine and Cancer Center, University of California at Irvine, Orange.
F L
FL
Meyskens
S S
SS
Emerson
D
D
Pelot
H
H
Meshkinpour
L R
LR
Shassetz
J
J
Einspahr
D S
DS
Alberts
E W
EW
Gerner
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D015317:Biogenic Polyamines / Q000378:metabolism*; D003111:Colonic Polyps / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D004334:Drug Administration Schedule; D000518:Eflornithine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
D015317:Biogenic Polyamines; D013096:Spermine; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine