The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: Results of a year-long phase IIb randomized placebo-controlled chemoprevention trial

被引:67
作者
Simoneau, Anne R. [1 ,2 ]
Gerner, Eugene W. [5 ]
Nagle, Ray [5 ]
Ziogas, Argyrios [2 ,4 ]
Fujikawa-Brooks, Sharon [2 ]
Yerushalmi, Hagit [5 ]
Ahlering, Thomas E. [2 ]
Lieberman, Ronald [6 ]
McLaren, Christine E. [2 ,4 ]
Anton-Culver, Hoda [2 ,4 ]
Meyskens, Frank L., Jr. [2 ,3 ]
机构
[1] Univ Calif Irvine, Dept Urol, Orange, CA 92868 USA
[2] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA
[3] Univ Calif Irvine, Dept Med, Orange, CA 92668 USA
[4] Univ Calif Irvine, Dept Epidemiol, Orange, CA 92668 USA
[5] Univ Arizona, Tucson, AZ USA
[6] Dept Chemoprevent Investigat Branch, Bethesda, MD USA
关键词
D O I
10.1158/1055-9965.EPI-07-0658
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Prostate cancer is a major health issue, and prevention of prostate cancer and/or its progression will yield benefits for men. Difluoromethylomithine (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. Conclusion: 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.
引用
收藏
页码:292 / 299
页数:8
相关论文
共 51 条
[1]  
Alberts DS, 2000, CANCER EPIDEM BIOMAR, V9, P1281
[2]   Chemoprevention of prostate cancer in men at high risk: Rationale and design of the reduction by dutasteride of prostate cancer events (reduce) trial [J].
Andriole, G ;
Bostwick, D ;
Brawley, O ;
Gomella, L ;
Tindall, D ;
Breed, S ;
Somerville, M ;
Rittmaster, R .
JOURNAL OF UROLOGY, 2004, 172 (04) :1314-1317
[3]   Cell transformation, invasion, and angiogenesis: A regulatory role for ornithine decarboxylase and polyamines? [J].
Auvinen, M .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1997, 89 (08) :533-537
[4]   Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention [J].
Barry, Elizabeth L. R. ;
Baron, John A. ;
Bhat, Shubha ;
Grau, Maria V. ;
Burke, Carol A. ;
Sandler, Robert S. ;
Ahnen, Dennis J. ;
Haile, Robert W. ;
O'Brien, Thomas G. .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (20) :1494-1500
[5]   Pretreatment predictors of posttreatment PSA doubling times for patients undergoing three-dimensional conformal radiotherapy for clinically localized prostate cancer [J].
Beard, C ;
Chen, MH ;
Cote, K ;
Loffredo, M ;
Renshaw, A ;
Hurwitz, M ;
D'Amico, AV .
UROLOGY, 2005, 66 (05) :1020-1023
[6]   THE DEVELOPMENT OF HUMAN BENIGN PROSTATIC HYPERPLASIA WITH AGE [J].
BERRY, SJ ;
COFFEY, DS ;
WALSH, PC ;
EWING, LL .
JOURNAL OF UROLOGY, 1984, 132 (03) :474-479
[7]   Androgen regulation of ornithine decarboxylase in human prostatic cells identified using differential display [J].
Betts, AM ;
Waite, I ;
Neal, DE ;
Robson, CN .
FEBS LETTERS, 1997, 405 (03) :328-332
[8]  
BOYLE JO, 1992, CANCER EPIDEM BIOMAR, V1, P131
[9]  
Calandra R. S., 1996, Acta Physiologica Pharmacologica et Therapeutica Latinoamericana, V46, P209
[10]   Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases [J].
Casero, Robert A., Jr. ;
Marton, Laurence J. .
NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (05) :373-390