Love R R, Jacoby R, Newton M A, Tutsch K D, Simon K, Pomplun M, Verma A K
Department of Medicine, University of Wisconsin School of Medicine, Madison, USA.
Cancer Epidemiol Biomarkers Prev. 1998 Nov;7(11):989-92.
DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. The goal of this study was to determine the effects of DFMO 0.5 g/m2/day as a single oral dose on polyamine and ODC levels in rectal, rectosigmoidal, and cecal colonic mucosae of individuals at risk for colon cancer because of a personal history of adenomatous polyps of the colon or a family history of colon cancer in at least one first-degree relative. A second goal was to determine toxicity of this treatment given over 1 year. Forty-five randomized subjects had a flexible sigmoidoscopy with no preparation and a colonoscopy after lavage preparation at baseline, a sigmoidoscopy with no preparation after 3 months, and both procedures (as at baseline) after 12 months, with mucosal biopsies taken from the rectosigmoid area (sigmoidoscopy) or rectal and cecal areas (colonoscopy) for evaluations of ODC and polyamine levels. Significantly decreased levels of putrescine and spermidine were found in rectosigmoid colonic mucosae of DFMO-treated (n = 24) compared with placebo (n = 21) subjects at 3 months (P = 0.03 and 0.04) and 12 months (P = 0.005, P = 0.004). Similar trends, none reaching statistical significance, were found for individual polyamine levels in rectal and cecal mucosae. No significant differences in ODC levels were detected marginally. There was evidence of global suppression of ODC and polyamine levels in the treatment group (P = 0.035). Three DFMO recipients (12.5%) developed clinically noticeable and audiologically demonstrated hearing loss, which was reversible and attributed to DFMO after 3 months (two subjects) and 12 months (one subject). The tissue polyamine changes demonstrated in this study are consistent with findings in other studies in colon and other tissues. The ototoxicity findings here suggest that investigation of other DFMO schedules, such as ones with a drug "holiday," will be a necessary step before Phase III chemoprevention studies can be pursued.
二氟甲基鸟氨酸（DFMO）是鸟氨酸脱羧酶（ODC）的不可逆抑制剂，ODC是哺乳动物多胺生物合成中的关键酶。本研究的目的是确定每天口服0.5 g/m²的DFMO单剂量对因有结肠腺瘤性息肉个人病史或至少一位一级亲属有结肠癌家族史而有患结肠癌风险的个体的直肠、直肠乙状结肠和盲肠结肠黏膜中多胺和ODC水平的影响。第二个目的是确定这种治疗持续1年的毒性。45名随机分组的受试者在基线时进行了无准备的乙状结肠镜检查和灌洗准备后的结肠镜检查，3个月后进行了无准备的乙状结肠镜检查，12个月后进行了这两种检查（与基线时相同），并从直肠乙状结肠区域（乙状结肠镜检查）或直肠和盲肠区域（结肠镜检查）采集黏膜活检样本，以评估ODC和多胺水平。与安慰剂组（n = 21）相比，在3个月（P = 0.03和0.04）和12个月（P = 0.005，P = 0.004）时，接受DFMO治疗的受试者（n = 24）的直肠乙状结肠黏膜中腐胺和亚精胺水平显著降低。在直肠和盲肠黏膜中的个体多胺水平也发现了类似趋势，但均未达到统计学意义。ODC水平未检测到显著差异。有证据表明治疗组的ODC和多胺水平受到整体抑制（P = 0.035）。三名接受DFMO治疗的受试者（12.5%）出现了临床上明显且经听力检查证实的听力损失，这种听力损失是可逆的，在3个月（两名受试者）和12个月（一名受试者）后归因于DFMO。本研究中显示的组织多胺变化与结肠和其他组织的其他研究结果一致。此处的耳毒性研究结果表明，在进行III期化学预防研究之前，研究其他DFMO给药方案，如设置药物“假期”的方案，将是必要的一步。
