Chemopreventive agents inhibit aberrant proliferation of the aneuploid phenotype in a colon epithelial cell line established from Apc 1638N [+/-] mouse.

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.