Skip to main content
Log in

Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice

  • Original Articles
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Furr BJ, Patterson JS, Richardson DN, Slater SR, Wakeling AE (1979) Tamoxifen. Pharmacological and biochemical properties of drug substances 2. American pharmaceutical association academy of pharmaceutical sciences. Washington, pp 355–399

    Google Scholar 

  2. Ashizawa T, Ishida H, Okabe M, Gomi K (1993) Effect of medroxyprogesterone acetate on antitumor efficacies and side effect on 5-fluorouracil (in Japanese with English abstract). Gan To Kagaku Ryoho 20:941–947

    CAS  PubMed  Google Scholar 

  3. Harper MJK, Walpole AL (1966) Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 212:87

    Article  CAS  PubMed  Google Scholar 

  4. Boccardo F, Guarneri D, Rubagotti A, Casertelli GL, Bentivoglio G, Conte N, Campanella G, Gaggero G, Comelli G, Zanardi S, Nicolo G (1984) Endocrine effects of tamoxifen in postmenopausal breast cancer patients. Tumori 70:61–68

    CAS  PubMed  Google Scholar 

  5. Fornander T, Rutqvist LE, Wilking N, Carstrom K, Schoultz BV (1993) Oestrogenic effects of adjuvant tamoxifen in postmenopausal breast cancer. Eur J Cancer 29A:497–500

    Article  CAS  PubMed  Google Scholar 

  6. Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS (1991) Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 83:1450–1459

    Article  CAS  PubMed  Google Scholar 

  7. Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN (1995) Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol 13:513–529

    CAS  PubMed  Google Scholar 

  8. Wakeling AE (1993) The future of new pure antiestrogens in clinical breast cancer. Breast Cancer Res Treat 25:1–9

    Article  CAS  PubMed  Google Scholar 

  9. Parker MG (1993) Action of “pure” antiestrogens in inhibiting estrogen receptor action. Breast Cancer Res Treat 26:131–137

    Article  CAS  PubMed  Google Scholar 

  10. Soule HD, Vazquez J, Long A, Albert S, Brennan M (1973) A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51:1409–1413

    CAS  PubMed  Google Scholar 

  11. Takeuchi T (1995) Chemo- and endocrino-therapy of breast carcinoma xenografts in the dormant or exponential growth phase (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 96:379–387

    CAS  PubMed  Google Scholar 

  12. Hanatani Y, Kubota T, Yamada Y, Tsuyuki K, Nakada M, Matsumoto S, Kumai K, Yoshino K, Ishibiki K, Abe O (1980) Experimental chemotherapy of human carcinomas serially transplanted to nude mice (in Japanese with English abstract). Nippon Gan Chiryo Gakkai Shi (J Jap Soc Cancer Ther) 15:1114–1120

    CAS  PubMed  Google Scholar 

  13. Masuike T, Watanabe I, Takemoto Y (1985) Quantitative method of 5-fluorouracil and its metabolites in biological samples using high performance liquid chromatography (in Japanese with English abstract). Yakugaku Zasshi 105:1058–1064

    CAS  PubMed  Google Scholar 

  14. Spears CP, Shahinian AH, Moran RG, Heidelberger C, Corbett TH (1982) In vivo kinetics of thymidylate synthetase inhibition in 5-fluorouracil-sensitive and- resistant murine colon adenocarcinoma. Cancer Res 42: 450–456

    CAS  PubMed  Google Scholar 

  15. Masuike T, Kikuchi K, Saito A, Hashimoto T, Takemoto Y (1995) Determination of 5-fluorouracil incorporated into RNA in tissue using gas chromatography-mass spectrometry (in Japanese with English abstract). Antibiot Chemother 11:162–167

    Google Scholar 

  16. Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E (1983) Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer. Cancer 51:581–588

    Article  CAS  PubMed  Google Scholar 

  17. Kardinal CG, Perry MC, Weinberg V, Wood W, Ginsberg S, Raju RN (1983) Chemoendocrine therapyvs chemotherapy alone for advanced breast cancer in postmenopausal women: preliminary report of a randomized study. Breast Cancer Res Treat 3:365–371

    Article  CAS  PubMed  Google Scholar 

  18. Mouridsen HT, Rose C, Engelsman E, Sylvester R, Rotmensz N (1985) Combined cytotoxic and endocrine therapy in postmenopausal patients with advanced breast cancer. A randomized study of CMFvs CMF plus tamoxifen. Eur J Cancer Clin Oncol 21:291–299

    Article  CAS  PubMed  Google Scholar 

  19. Viladiu P, Alonso MC, Avella A, Beltran M, Borras J, Ojeda B, Bosch FX (1985) Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients. A randomized trial. Cancer 56:2745–2750

    Article  CAS  PubMed  Google Scholar 

  20. Falkson G, Falkson HC, Glidewell O, Weinberg V, Leone L, Holland JF (1979) Improved remission rates and remission duration in young women with metastatic breast cancer following combined oophorectomy and chemotherapy. Cancer 43:2215–2222

    Article  CAS  PubMed  Google Scholar 

  21. Cavalli F, Beer M, Marts G, Jungi WF, Alberto P, Obrecht JP, Mermillod B, Brunner KW (1983) Concurrent or sequential use of cytotoxic chemotherapy and hormone treatment in advanced breast cancer: report of the Swiss group for clinical cancer research. Br Med J 286:5–8

    Article  CAS  Google Scholar 

  22. Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia (1986) A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol 4:186–193

    Google Scholar 

  23. Kiang DT, Gay J, Goldman A, Kennedy BJ (1985) A randomized trial of chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 313:1241–1246

    Article  CAS  PubMed  Google Scholar 

  24. Watanabe O (1994) Experimental chemoendocrine therapy of human breast carcinoma xenograft serially transplanted into nude mice (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 95:263–270

    CAS  PubMed  Google Scholar 

  25. Kubota T, Josui K, Ishibiki K, Abe O, Yamada Y, Asanuma F, Kawamura E, Kou J, Shiina E (1990) Experimental combined chemo- and endocrino-therapy of UFT and tamoxifen on human breast carcinoma xenografts serially transplanted into nude mice (in Japanese with English abstract). Nippon Gan Chiryo Gakkai Shi (J Jap Soc Cancer Ther) 25:2767–2773

    CAS  PubMed  Google Scholar 

  26. Benz C, Santos G, Cadman ED (1983) Tamoxifen and 5-fluorouracil in breast cancer: modulation of cellular RNA. Cancer Res 43:5304–5308

    CAS  PubMed  Google Scholar 

  27. Benz C, Cadman ED, Gwin J, Wu T, Amara J, Eisenfeld A, Dannies P (1983) Tamoxifen and 5-fluorouracil in breast cancer: cytotoxic synergism in vitro. Cancer Res 43:5298–5303

    CAS  PubMed  Google Scholar 

  28. Sato Y (1989) Experimental studies on the effect of chemoendocrine therapy on DMBA induced rat mammary cancer (in Japanese with English abstract). J Nihon Univ Med Assoc 48:413–421

    CAS  Google Scholar 

  29. Yamanoto H, Morimoto T, Monden Y (1989) Effect of chemoendocrine therapy on DMBA-induced rat mammary carcinoma (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 90:1786–1792

    Google Scholar 

  30. Kondo T, Imaizumi M, Taguchi T, Abe O, Hattori T, Wakui A, Kitano M (1987) A model for sensitivity determination of anticancer agents against human cancer using nude mice (in Japanese with English abstract). Gan To Kagaku Ryoho 14:680–686

    CAS  PubMed  Google Scholar 

  31. Koh J (1988) Experimental chemo- and chemoendocrine therapy of human breast carcinomas serially transplanted into nude mice (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 89:91–102

    CAS  PubMed  Google Scholar 

  32. Suzuki M (1992) Flow cytometric analysis of effects of chemohormonal agents on the cell cycle distribution of MCF-7 cells (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 93:71–80

    CAS  PubMed  Google Scholar 

  33. Today RA, Crissman HA (1972) Use of flow microflurometry in detailed analysis of effects of chemical agents on cell cycle progression. Cancer Res 32:2726–2732

    Google Scholar 

  34. Nakamura A (1988) Experimental and clinical study on flow cytometric DNA analysis of human breast carcinoma (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 89:737–746

    CAS  PubMed  Google Scholar 

  35. Darnenberg PV (1977) Thymidylate synthetase—a target engyme in cancer chemotherapy. Biochim Biophys Acta 473:73–92

    Google Scholar 

  36. Cory JG, Breland JC, Carter GL (1979) Effect of 5-fluorouracil on RNA metabolism in Novikoff hepatoma cells. Cancer Res 39:4905–4913

    CAS  PubMed  Google Scholar 

  37. Ardalan B, Cooney DA, Jayaram HN, Carrico CK, Glazer RI, Macdonald J, Schein PS (1980) Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil. Cancer Res 40:1431–1437

    CAS  PubMed  Google Scholar 

  38. Ueki H (1987) Synergistic effect of cell kinetics-directed chemoendocrine therapy on experimental mammary tumors (in Japanese with English abstract). Nippon Geka Gakkai Zasshi (J Jpn Surg Soc) 88: 1576–1583

    CAS  PubMed  Google Scholar 

  39. Maybaum J, Ullman B, Mandel HG, Day JL, Sadee W (1980) Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. Cancer Res 40:4209–4215

    CAS  PubMed  Google Scholar 

  40. Kubota T, Fujita S, Kodaira S, Yamamoto T, Josui K, Arisawa Y, Suto A, Ishibiki K, Abe O, Mabuchi K, Fuse M (1991) Antitumor activity of fluoropyrimidines and thymidylate synthetase inhibition. Jpn J Cancer Res 82:476–482

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ogasawara, Y., Doihara, H., Shiroma, K. et al. Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice. Surg Today 29, 149–156 (1999). https://doi.org/10.1007/BF02482240

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02482240

Key Words

Navigation