Tamoxifen and 5-fluorouracil in breast cancer: cytotoxic synergism in vitro.
The cytokinetic and cytotoxic interactions involved in combining tamoxifen, methotrexate, and 5-fluorouracil were studied in two 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. Both 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 microM could be prevented by 1 nM estradiol. After exposure of 47-DN cells to 10 microM 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 G0-1 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 either 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.
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use* / Q000633:toxicity; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use* / Q000633:toxicity
D011959:Receptors, Estradiol; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; D005472:Fluorouracil; D008727:Methotrexate