The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: Results of a year-long phase IIb randomized placebo-controlled chemoprevention trial
The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: Results of a year-long phase IIb randomized placebo-controlled chemoprevention trial
复制标题
DOI：
10.1158/1055-9965.epi-07-0658
复制
发表时间：
2008-02-01
影响因子：
3.8
通讯作者：
Meyskens, Frank L., Jr.
中科院分区：
文献类型：
--
作者：
Simoneau, Anne R.;Gerner, Eugene W.;Meyskens, Frank L., Jr.
背景：前列腺癌是一个主要的健康问题，预防前列腺癌和/或其进展将为男性带来好处。二氟甲基鸟氨酸 (DFMO) 是一种抗增殖剂，可抑制鸟氨酸脱羧酶（多胺途径中的第一种酶），并已作为治疗和化学预防剂进行研究。前列腺具有高水平的组织多胺，并且在体外和体内均表现出对 DFMO 的敏感性。方法：81 名男性参加了一项为期 1 年的安慰剂或 DFMO 随机试验。在基线和 12 个月后进行前列腺体积测定和前列腺活检以了解组织学和多胺含量。评估了其他生物标志物变量，包括总和游离前列腺特异性抗原以及前列腺特异性抗原倍增时间。结果：与基线相比，1 年时接受 DFMO 的男性前列腺体积增加 (0.14 cm(3)) 比服用安慰剂的男性 (2.95 cm(3)；p = 0.0301) 更小。此外，DFMO 使前列腺腐胺水平降低 60.8%，而安慰剂组则增加 139.5%（P = 0.0014）。按鸟氨酸脱羧酶基因型分层显示，DFMO 减少了 AA + GA 组的前列腺体积（P = 0.029）和腐胺水平（P = 0.0053），但在 GG 组中没有。没有出现3级或4级毒性。没有临床耳毒性，听力图上有 1 例亚临床 2 级听力下降。结论：在这项随机安慰剂对照试验中，DFMO 诱导前列腺腐胺水平和前列腺生长速度降低。应进一步研究该化合物治疗前列腺癌或前列腺增生的潜力。
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.