Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz
Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz
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DOI：
10.1172/jci118904
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发表时间：
1996-09-01
影响因子：
15.9
通讯作者：
Clapper, ML
中科院分区：
文献类型：
--
作者：
ODwyer, PJ;Szarka, CE;Clapper, ML
长期接触致突变物质与个体患结直肠癌的风险密切相关，吡噻硫酮作为化学预防剂的临床研究得到了其在各种组织中诱导解毒酶表达及其对动物中化学诱导结直肠肿瘤形成的保护活性的支持。本研究的目标是：确定吡噻硫酮是否可以诱导人体组织中的解毒基因表达；确定有效的无毒剂量以进行更广泛的临床测试；并建立结肠粘膜效应与更容易获得的组织（外周单核细胞）效应之间的关系。在一项剂量探索研究中，24 名可评估的结直肠癌高危患者接受了奥替普拉 125、250、500 或 1,000 mg/m(2) 单次口服剂量的治疗。对连续血液样本和结肠粘膜活检的生化分析显示，较低剂量水平下谷胱甘肽转移酶活性增加。在较高剂量下没有观察到这些效应。在所有剂量下，两种组织中解毒酶基因表达均观察到更明显的变化，外周单核细胞和结肠中γ-谷氨酰半胱氨酸合成酶(gamma-GCS)和DT-心肌黄酶的mRNA含量在给药后增加，在治疗后第2-4天达到峰值，并在随后的7-10天下降到基线。在250 mg/m(2)时，γ-GCS诱导结肠粘膜基因表达的程度达到峰值5.75倍，DT-心肌黄酶达到峰值4.14倍。更高的剂量并不更有效。在基线和峰值时，外周单核细胞和结肠粘膜之间的γ-GCS和DT-心肌黄酶水平密切相关（P小于或等于0.001）。这些发现表明，低剂量的最小毒性药物的施用可以调节癌症高危个体组织中解毒基因的表达。此外，外周单核细胞可以用作正常结肠粘膜对药物施用的转录反应的非侵入性替代终点生物标志物。
Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer, Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals, The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective nontoxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m(2) as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the lower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses, Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m(2); higher doses were not more effective. Levels of gamma-GCS and DT-diaphorase correlated closely (P less than or equal to 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak, These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer, Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration.