Sequential methotrexate (MTX) and 5-fluorouracil (FU) in human tumor xenografts

  • K. Wayss
  • R. Herrmann
  • J. Mattern
  • M. Volm


Human and animal tumor-lines heterotransplanted in nude mice were treated with MTX and FU sequentially. In order to investigate the relationship between tumor response and drug toxicity sequence, time and dose of both MTX and FU were varied. Pretreatment with MTX followed by FU with intervals of 3 or 24 h produced superior therapeutic results when compared to single administration of MTX or FU, simultaneous treatment, or the reverse sequence. In the MTX followed by FU regimen, dose reduction of either MTX or FU tended to decrease the anti-tumor effect. To investigate the toxic effects of different regimens, tumor-free nude mice were treated with MTX and FU the same way as the tumor-bearing animals. In this case, toxicity (weight loss, leukopenia) was more pronounced in those schedules with the best therapeutic results. However, toxicity appears to be more clearly related to the applied FU-dose.

Key words

Sequential Methotrexate 5-Fluorouracil Nude mouse Heterotransplantate 


  1. 1.
    Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini C, Bajetta E, Musumeci R, Veronesi U: Combination chemotherapy as an adjuvant treatment in operable breast cancer.New Engl J Med 294, 405 (1976).PubMedGoogle Scholar
  2. 2.
    Benz C, Cadman E: Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma HCT-8.Cancer Res 41, 994 (1981).PubMedGoogle Scholar
  3. 3.
    Benz C, Tillis T, Tattelman E, Cadman E: Optimal scheduling of methotrexate and 5-fluorouracil in human breast cancer.Cancer Res 42, 2081 (1982).PubMedGoogle Scholar
  4. 4.
    Cadman E, Heimer R, Davis L: Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism.Science 205, 1135 (1979).PubMedCrossRefGoogle Scholar
  5. 5.
    Fernandes D J, Bertino J R: 5-Fluorouracilmethotrexate synergy: enhancement of 5-fluorodeoxyuridylate binding to thymidylate synthetase by dihydropteroylglutamates.Proc Natn Acad Sci, USA 76, 5663 (1980).CrossRefGoogle Scholar
  6. 6.
    Benz C, Schoenberg M, Choti M, Cadman E: Schedule-dependent cytotoxicity of methotrexate and 5-fluorouracil in human colon and breast tumor cell lines.J Clin Invest 66, 1162 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    Bertino J R, Sawicki W L, Lindquist C A, Gupta V S: Schedule-dependent antitumor effects of methotrexate and 5-fluorouracil.Cancer Res 37, 327 (1977).PubMedGoogle Scholar
  8. 8.
    Mulder J H, Smink T, van Putten L M: 5-Fluorouracil and methotrexate combination chemotherapy: the effect of drug scheduling.Eur J Cancer Clin Oncol 17, 831 (1981).PubMedCrossRefGoogle Scholar
  9. 9.
    Wayss K, Herrmann R, Mattern J, Volm M: Sequence, time- and dose-dependence of the therapeutic effects of methotrexate and 5-fluorouracil in human tumour xenografts. Georgii A.Therapie maligner Tumoren. Verh Dtsch Krebs Ges Vol. 4, p. 140. Stuttgart, Gustav Fischer Verlag (1983).Google Scholar
  10. 10.
    Cantrell J E Jr, Brunet R, Lagarde C, Schein P S, Smith F P: Phase II study of sequential methotrexate-5-FU therapy in advanced measurable colorectal cancer.Cancer Treat Rep 66, 1563 (1982).PubMedGoogle Scholar
  11. 11.
    Gewirtz A M, Cadman E: Preliminary report on the efficacy of sequential methotrexate and 5-fluorouracil in advanced breast cancer.Cancer 47, 2552 (1981).PubMedCrossRefGoogle Scholar
  12. 12.
    Herrmann R, Spehn J, Beyer J H, von Franqué U, Schmieder A, Holzmann K: Sequential methotrexate and 5-fluorouracil. Improved response rate in metastatic colorectal cancer.J Clin Onc (in press).Google Scholar
  13. 13.
    Herrmann R, Schroeder M, Tigges F, Bartsch H, Jungi F, Manegold C, Fritze D: Sequential methotrexate and 5-fluorouracil in breast cancer resistant to the conventional application of these drugs.Cancer Treat Rep (in press).Google Scholar
  14. 14.
    Klein H O, Dias Wickramanayake P, Dieterle F, Mohr R, Oerkermann H, Brock J, Beyer D, Gross R: Chemotherapieprotokoll zur Behandlung des metastasierenden Magenkarzinoms. Methotrexat, Adriamycin und 5-Fluorouracil.Dtsch Med Wochenschr 107, 1708 (1982).PubMedCrossRefGoogle Scholar
  15. 15.
    Solan A, Vogl S E, Kaplan B H, Berenzweig M, Richard J, Lanham R: Sequential chemotherapy of advanced colorectal cancer with standard or high-dose methotrexate followed by 5-fluorouracil.Med Pediatr Oncol 10, 145 (1982).PubMedCrossRefGoogle Scholar
  16. 16.
    Tisman G, Wu S J: Effectiveness of intermediate dose methotrexate and high dose 5-fluorouracil as sequential combination chemotherapy in refractory breast cancer and as primary therapy in metastatic adenocarcinoma of the colon.Cancer Treat Rep 64, 829 (1980).PubMedGoogle Scholar
  17. 17.
    Weinerman B, Schacter B, Schipper H, Bowman D, Levitt M: Sequential methotrexate and 5-FU in the treatment of colorectal cancer.Cancer Treat Rep 66, 1553 (1982).PubMedGoogle Scholar
  18. 18.
    Mattern J, Jaeger S, Wayss K, Volm M: Therapeutic response of human lung tumour xenografts to cyclophosphamide.Anticancer Res 2, 355 (1982).PubMedGoogle Scholar
  19. 19.
    Mattern J, Keppler B, Volm M: Preclinical evaluation of diethoxy-(1-phenyl-1,3-butanedionato) titanium (IV) in human tumour xenografts.Arzneimittelforsch (in press).Google Scholar
  20. 20.
    Mattern J, Haag D, Wayss K, Volm M: Significance of proliferation for the growth of xenografted human tumours in nude mice.Anticancer Res 1, 15 (1981).Google Scholar
  21. 21.
    Kufe D W, Egan E M: Enhancement of 5-fluorouracil incorporation into human lymphoblast ribonucleic acid.Biochem Pharmacol 30, 129 (1981).PubMedCrossRefGoogle Scholar
  22. 22.
    Houghton J A, Tice A J, Houghton P J: The selectivity of action of methotrexate in combination with 5-fluorouracil in xenografts of human colon adenocarcinomas.Molec Pharmacol 22, 771 (1982).Google Scholar
  23. 23.
    Herrmann R, Kunz W, Osswald H, Ritter M, Port R: Sequential methotrexate and 5-fluorouracil in sarcoma 180in vivo. Effects on 5-FU kinetics.Proc 13th Int Congr Chemother 286, 39 (1983).Google Scholar
  24. 24.
    Ringborg U, Ewert G, Kinnman J, Lundquist P G, Strander H: Sequential methotrexate-5-fluorouracil treatment of squamous cell carcinoma of the head and neck.Cancer 52, 971 (1983).PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1985

Authors and Affiliations

  • K. Wayss
    • 1
  • R. Herrmann
    • 2
  • J. Mattern
    • 1
  • M. Volm
    • 1
  1. 1.German Cancer Research CenterInstitute of Experimental PathologyHeidelbergWest Germany
  2. 2.Medizinische UniversitätsklinikHeidelbergWest Germany

Personalised recommendations