The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: results of a year-long phase IIb randomized placebo-controlled chemoprevention trial.
BACKGROUND
Prostate cancer is a major health issue, and prevention of prostate cancer and/or its progression will yield benefits for men. Difluoromethylornithine (DFMO) is an antiproliferative agent, inhibiting ornithine decarboxylase, the first enzyme in the polyamine pathway, and has been studied as a therapeutic and chemopreventive agent. The prostate has high levels of tissue polyamines and has shown sensitivity to DFMO both in vitro and in vivo.


METHODS
Eighty-one men participated in a 1-year randomized trial of placebo or DFMO. Prostate volume determination and biopsy of the prostate for histology and polyamine content were done at baseline and after 12 months. Other biomarker variables were assessed, including total and free prostate-specific antigen and prostate-specific antigen doubling time.


RESULTS
Compared with baseline, men receiving DFMO had a smaller increase in prostate volume (0.14 cm(3)) than those on placebo (2.95 cm(3); P = 0.0301) at 1 year. In addition, DFMO caused a 60.8% reduction of prostate putrescine levels compared with a 139.5% increase in the placebo arm (P = 0.0014). Stratification by ornithine decarboxylase genotype showed that DFMO reduced prostate volume (P = 0.029) and putrescine levels (P = 0.0053) in the AA + GA group but not in the GG group. There were no grade 3 or 4 toxicities. There was no clinical ototoxicity, with one subclinical grade 2 hearing decline on audiogram.


CONCLUSIONS
In this randomized placebo-controlled trial, DFMO induced a decrease of prostate putrescine levels and rate of prostate growth. The potential of this compound for prostate cancer or hyperplasia should be further studied.
Simoneau
Anne R
AR
Department of Medicine, University of California, Irvine, 101 The City Drive, Route 81, Building 55, Room 304, Orange, CA 92868, USA. asimonea@uci.edu
Gerner
Eugene W
EW
Nagle
Ray
R
Ziogas
Argyrios
A
Fujikawa-Brooks
Sharon
S
Yerushalmi
Hagit
H
Ahlering
Thomas E
TE
Lieberman
Ronald
R
McLaren
Christine E
CE
Anton-Culver
Hoda
H
Meyskens
Frank L
FL
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood; D001706:Biopsy; D000518:Eflornithine / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011073:Polyamines / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011467:Prostate / Q000187:drug effects* / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011073:Polyamines; D017430:Prostate-Specific Antigen; D000518:Eflornithine