Katdare M, Kopelovich L, Telang N
Chemoprevention Research Laboratory, Strang Cancer Prevention Center, New York, New York 10021, USA.
Ann N Y Acad Sci. 2001 Dec;952:169-74. doi: 10.1111/j.1749-6632.2001.tb02738.x.
Loss of function of the adenomatous polyposis coli (APC) tumor suppressor gene predisposes for familial adenomatous polyposis (FAP) syndrome. The Apc gene knockout mice exhibit accelerated intestinal carcinogensis modifiable by diverse pharmacological agents. Present experiments utilized the Apc[+/-] 1638N COL colon epithelial cell line (origin: histologically normal colon) as the model. Retinoid receptor modulator 9-cis-retinoic acid (9-cis-RA), ornithine decarboxylase inhibitor difluoromethyl ornithine (DFMO), and nonselective cyclooxygenase inhibitor sulindac (SUL) represented the chemopreventive test compounds. Population doubling, cell cycle progression, and anchorage-independent growth provided mechanistic end points for chemopreventive efficacy. Treatment of 1638N COL cells with 9-cis-RA, DFMO and SUL produced a dose-dependent cytostatic growth arrest by decreasing the number of population doublings and altering aneuploid G0/G1:S+G2/M ratio. The clonally expanded 1638N-Cl1 cells selected for anchorage-independent growth exhibited decreased anchorage-independent colony formation in response to treatment with the three test compounds. Susceptibility of preneoplastic 1638N COL cells to mechanistically distinct chemopreventive agents validates a unique epithelial cell culture model for FAP syndrome, and facilitates investigations on Apc regulated colon carcinogenesis and cancer prevention.
腺瘤性结肠息肉病（APC）肿瘤抑制基因功能丧失易引发家族性腺瘤性息肉病（FAP）综合征。Apc基因敲除小鼠表现出加速的肠道癌变，可被多种药物改变。目前的实验使用Apc[+/-] 1638N COL结肠上皮细胞系（来源：组织学正常的结肠）作为模型。视黄酸受体调节剂9-顺式视黄酸（9-cis-RA）、鸟氨酸脱羧酶抑制剂二氟甲基鸟氨酸（DFMO）和非选择性环氧化酶抑制剂舒林酸（SUL）代表化学预防测试化合物。群体倍增、细胞周期进程和不依赖贴壁生长为化学预防效果提供了机制性终点。用9-cis-RA、DFMO和SUL处理1638N COL细胞，通过减少群体倍增数和改变非整倍体G0/G1:S+G2/M比率，产生了剂量依赖性的细胞生长抑制。为不依赖贴壁生长而选择的克隆扩增的1638N-Cl1细胞，在接受三种测试化合物处理后，不依赖贴壁的集落形成减少。癌前1638N COL细胞对机制不同的化学预防剂的敏感性验证了一种针对FAP综合征的独特上皮细胞培养模型，并有助于对Apc调节的结肠癌发生和癌症预防进行研究。
