The purpose of this study was to determine if potassium channel activity is required for the proliferation of MCF-7 human mammary carcinoma cells. We examined the sensitivities of proliferation and progress through the cell cycle to each of nine potassium channel antagonists. Five of the potassium channel antagonists produced a concentration-dependent inhibition of cell proliferation with no evidence of cytotoxicity following a 3-day or 5-day exposure to drug. The IC,, values for these five drugs, quinidine (25 pM), glibenclamide (50 pM), linogliride (770 pM), 4-aminopyridine (1.6 mM), and tetraethylammonium (5.8 mM) were estimated from their respective concentration-response curves. Four other potassium channel blockers were tested at supra-maximal channel blocking concentrations, including charybdotoxin (200 nM), iberiotoxin (1 00 nM), margatoxin (1 0 nM), and apamin (500 nM), and they had no effect on MCF-7 cell proliferation, viability, or cell cycle distribution. O f the five drugs that inhibited proliferation, only quinidine, glibenclamide, and linogliride also affected the cell cycle distribution. Cell populations exposed to each of these drugs for 3 days showed a statistically significant accumulation in GOIG1 phase and a significant proportional reduction in S phase and G2/M phase cells. The inhibition o f cell proliferation correlated significantly with the extent of cell accumulation in GOiG1 phase, and the threshold concentrations for inhibition of growth and CO/G1 arrest were 0 1995 WILEY-LISS. INC. al., 1992), and human A431 carcinoma cells (Peppelenbosch et al., 1991), phytohemagglutinin-and IL2-stimulated human T lymphocytes (Deutsch et al., 1986(Deutsch et al., , 1991;; Matteson and Deutsch et al., 19841, and EGF-and insulin-stimulated mouse mammary epithelial cells (Enomoto et al., 1986a,b). In MCF-7 cells, the activity of a calcium-activated potassium channel was found to be higher during logarithmic than plateau phases of