CELL-PROLIFERATION KINETICS OF MCF-7 HUMAN MAMMARY-CARCINOMA CELLS IN CULTURE AND EFFECTS OF TAMOXIFEN ON EXPONENTIALLY GROWING AND PLATEAU-PHASE CELLS

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (9) , 3998-4006
Abstract
MCF-7 human mammary carcinoma cells were inoculated into 150-scm flasks at 3 .times. 105 cells/flask, and after a lag period of .apprx. 48 h, these cells grew exponentially for 5 days with a mean population doubling time of .apprx. 24 h. During exponential growth, 80-90% of cells were in the ''''rapidly cycling'''' pool, the clonogenic fraction was 50-60%, and the mean percentage of cells in the G0-G1, S, and G2 + M phases of the cell cycle was 48.9 .+-. 0.6% (S.E.), 39.4 .+-. 0.6%, and 11.6 .+-. 0.3%, respectively. These parameters changed rapidly between days 7 and 13 when plateau phase was reached. Between days 13 and 18, 74.8 .+-. 0.7% of cells were in G0-G1, 15.3 .+-. 0.4% were in S, and 9.8 .+-. 0.6% were in G2 + M phase. Only .apprx. 30% of these cells were cycling rapidly, and the clonogenic fraction had fallen to < 10%. Tamoxifen induced a dose-dependent decrease in the growth rate of exponentially growing cells, which was accompanied by a dose-dependent increase in percentage of G0-G1-phase cells, and a decline in percentage of S-phase cells. At doses .gtoreq. 10 .mu.M, a 24-h pulse of tamoxifen was cytotoxic to exponentially growing cells. Plateau-phase cells were less sensitive to these effects of tamoxifen. In an attempt to define the kinetic basis of the G0-G1 accumulation induced by tamoxifen, asynchronous MCF-7 cells were pretreated for 42 h with various doses of tamoxifen, and the rate of efflux of cells from the G0-G1 phase of the cell cycle was assessed. Tamoxifen decreased the rate at which the slowly cycling cells traversed G1. Simultaneous treatment with estradiol returned these parameters to control values at doses of tamoxifen .ltoreq. 5 .mu.M, partially reversed the effect of 7.5 .mu.M tamoxifen, but was without effect on the arrest of cell cycle progression induced by 10 .mu.M tamoxifen. Cells accumulate in G0-G1 following tamoxifen treatment due to an increase in the proportion of slowly cycling cells at the expense of a population of rapidly cycling cells, which appear to be relatively uninfluenced by the drug.