Modulation of 5-Fluorouracil Toxicity via Estrogen Receptor
Modulation of 5-fluorouracil (FUra) metabolism and toxicity by methotrexate (MTX) and other antimetabolites occurs in many cultured tumor cell lines, including the estrogen receptor positive human mammary carcinoma, 47-DN. The growth rate of this cell line depends on exogenously administered insulin and estradiol, and can be reversibly inhibited by the antiestrogen, tamoxifen (TAM).
47-DN cell-cycle kinetics are altered by doses of TAM which suppress the synthesis of estrogen and progesterone receptors. In cloning assays, TAM is synergistic with FUra and sequentially combined MTX-KFUra; in biochemical assays, TAM inhibits FUra intracellular accumulation and incorporation into RNA. This unique form of drug modulation may represent a form of “complementary inhibition,” and supports clinical trials in breast cancer suggesting that TAM + FUra-containing chemotherapy is superior to chemotherapy alone.
KeywordsIntracellular Accumulation Clonal Growth Complementary Inhibition Antiestrogen Action Cloning Assay
Unable to display preview. Download preview PDF.
- 1.L.G. Kardinal, W.L. Donegan and J.S. Spratt, eds. Chemotherapy, in: “Cancer of the Breast,” W.B. Saunders Company, Philadelphia. 405–447 (1979).Google Scholar
- 3.C. Benz, and E. Cadman. Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma, HCT-8. Cancer Res. 41: 994–999 (1981).Google Scholar
- 6.K. Horwitz, D. Zava, A. Thilagar, E. Jensen, and W. McGuire. Steroid receptor analysis of nine human breast cancer cell lines. Cancer Res. 38: 2434–2437 (1978).Google Scholar
- 17.K. Horwitz and W. McGuire. Nuclear mechanisms of estrogen action: Effects of estradiol and antiestrogens on estrogen receptors and nuclear receptor processing. J. Biol. Chem. 253: 8185–8191 (1978).Google Scholar
- 8.N. Waseda, Y. Kato, H. Imura, and M. Kurata. Effects of Tamoxifen on estrogen and progesterone receptors in human breast cancer. Cancer Res. 41: 1984–1988 (1981).Google Scholar
- 9.S. Zietz. FPi analysis-theoretical outline of a new method to analyze time sequences of DNA histograms. Cell Tissue Kinet. 13: 461–471 (1980).Google Scholar
- 10.E. Cadman, R. Heimer and C. Benz. The influence of methotrexate pretreatment on 5-fluorouracil metabolism in L1210 cells. J. Biol. Chem. 256: 1695–1704 (1981).Google Scholar
- 12.A. Sartorelli and B. Booth. The synergistic antineoplastic activity of combinations of mitomycins with either 6-thioguanine of 5-fluorouracil. Cancer Res. 25: 1393–1499 (1965).Google Scholar
- 13.K. Horwitz and W. McGuire. Studies on mechanisms of estrogen and antiestrogen action in human breast cancer. Recent Results Cancer Res. 71: 45–58 (1980).Google Scholar
- 15.C. Fabian, L. Sternson, and M. Barnett. Clinical pharmacology of tamoxifen in patients with breast cancer: comparison of traditional and loading dose schedules. Cancer Treat Rep. 64: 765–773 (1980).Google Scholar
- 16.J. Speyer, J. Collins, R. Dedrick, M. Brennan, A. Buckpitt, H. Londer, V. DeVita, Jr., and C. Myers. Phase I and Pharmacological studies of 5-fluorouracil administered intraperitoneal. Cancer Res. 40: 567–572 (1980).Google Scholar
- 17.H. Mouridsen, T. Palshof, E. Engelsman, and R. Sylvester. CMF versus CMF plus tamoxifen in advanced breast cancer in post-menopausal women: An EORTC trial, in: “Breast Cancer — Experimental and Clinical Aspects,” H.T. Mouridsen and T. Palshof, eds., Pergamon Press, Oxford. 119–123 (1980).Google Scholar
- 18.B. Fisher, C. Redmond, A. Brown, N. Wolmark, J. Wittliff, E. Fisher, D. Plotkin, D. Bowman, S. Sachs, J. Wolter, R. Frelick, R. Desser, N. LiCalzi, P. Geggie, T. Campbell, E. Elias, D. Prager, P. Koontz, H. Volk, N. Dimitrov, B. Gardner, H. Lerner, H. Shibata, and other NSABP investigators. Treatment of primary breast cancer with chemotherapy and tamoxifen. N.E.J.M. 305: 1–6 (1981).Google Scholar