TAMOXIFEN AND 5-FLUOROURACIL IN BREAST-CANCER - CYTO-TOXIC SYNERGISM INVITRO

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (11) , 5298-5303
Abstract
The cytokinetic and cytotoxic interactions involved in combining tamoxifen, methotrexate and 4-fluorouracil were studied in 2 hormone-dependent human breast cancer cell lines, 47-DN and MCF-7. These cells had measurable cytosol and nuclear estrogen receptor and cytosol progesterone receptor. Growth of the MCF-7 cells in medium containing gelding serum was stimulated maximally by addition of 10 pM estradiol. MCF-7 and 47-DN cells showed dose-dependent in vitro growth inhibition on exposure to tamoxifen, and toxicity from tamoxifen at concentrations up to 10 .mu.M could be prevented by 1 nM estradiol. After exposure of 47-DN cells to 10 .mu.m tamoxifen, cytosol progesterone and nuclear estrogen receptor levels were still detectable at 30 and 60% of control values. With this same concentration of tamoxifen, 47-DN cells in S phase declined 50% in association with a buildup of GO-1 cells. By clonogenic assay, tamoxifen enhanced 47-DN and MCF-7 cytotoxicity to 5-fluorouracil and 5-fluorouridine, but not to methotrexate alone. When given concurrently or using a pretreatment-synchronizing schedule, tamoxifen enhanced markedly the growth inhibition of sequentially combined methotrexate and 5-fluorouracil. Isobologram analysis was used to prove that the cytotoxic interaction between tamoxifen and 5-fluorouracil was synergistic.