Meyskens F L, Gerner E W, Emerson S, Pelot D, Durbin T, Doyle K, Lagerberg W
Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, USA.
J Natl Cancer Inst. 1998 Aug 19;90(16):1212-8. doi: 10.1093/jnci/90.16.1212.
Polyamines (e.g., putrescine, spermidine, and spermine) are required for optimal cell growth. Inhibition of polyamine synthesis suppresses carcinogen-induced epithelial cancers, including colon cancer, in animal models. In a short-term phase IIa trial, we determined that low doses of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (an enzyme involved in polyamine synthesis), reduced the polyamine content of normal-appearing rectal mucosa of subjects with a prior history of resected colon polyps. In a follow-up study, we have attempted to determine the lowest dose of DFMO that can suppress the polyamine content of rectal mucosa over a course of 1 year with no or minimal side effects.
Participants were randomly assigned to daily oral treatment with a placebo or one of three doses (0.075, 0.20, or 0.40 g/m2) of DFMO. Baseline and serial determinations of polyamine levels in rectal mucosa and extensive symptom monitoring (including audiometric measurements, since DFMO causes some reversible hearing loss at higher doses) were performed over a 15-month period.
DFMO treatment reduced putrescine levels in a dose-dependent manner. Following 6 months of treatment, doses of 0.20 and 0.40 g/m2 per day reduced putrescine levels to approximately 34% and 10%, respectively, of those observed in the placebo group. Smaller decreases were seen in spermidine levels and spermidine:spermine ratios. Polyamine levels increased toward baseline values after discontinuation of DFMO. Although there were no statistically significant differences among the dose groups with respect to clinically important shifts in audiometric thresholds and nonaudiologic side effects, statistically significant higher dropout and discontinuation rates were observed in the highest dose group.
Polyamine levels in rectal mucosa can be continuously suppressed by daily oral doses of DFMO that produce few or no side effects. A dose of 0.20 g/m2 can be used safely in combination phase IIb or single-agent phase III chemoprevention trials.
多胺（如腐胺、亚精胺和精胺）是细胞最佳生长所必需的。在动物模型中，抑制多胺合成可抑制致癌物诱导的上皮癌，包括结肠癌。在一项短期IIa期试验中，我们确定低剂量的α-二氟甲基鸟氨酸（DFMO），一种鸟氨酸脱羧酶（参与多胺合成的一种酶）抑制剂，可降低有结肠息肉切除史受试者正常外观直肠黏膜中的多胺含量。在一项后续研究中，我们试图确定在1年时间内能够抑制直肠黏膜多胺含量且无或仅有最小副作用的DFMO最低剂量。
参与者被随机分配接受每日口服安慰剂或三种剂量（0.075、0.20或0.40 g/m²）之一的DFMO治疗。在15个月期间，对直肠黏膜中的多胺水平进行基线和连续测定，并进行广泛的症状监测（包括听力测定，因为DFMO在较高剂量时会导致一些可逆性听力损失）。
DFMO治疗以剂量依赖方式降低了腐胺水平。治疗6个月后，每天0.20和0.40 g/m²的剂量分别将腐胺水平降低至安慰剂组观察值的约34%和10%。亚精胺水平和亚精胺：精胺比值的下降幅度较小。停用DFMO后，多胺水平向基线值升高。尽管在听力阈值的临床重要变化和非听力副作用方面，各剂量组之间没有统计学上的显著差异，但在最高剂量组中观察到统计学上显著更高的退出和停药率。
每日口服DFMO可连续抑制直肠黏膜中的多胺水平，且几乎不产生副作用或无副作用。0.20 g/m²的剂量可安全用于联合IIb期或单药III期化学预防试验。
