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

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Abstract

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.

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References

  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).

    PubMed  CAS  Google Scholar 

  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).

    PubMed  CAS  Google Scholar 

  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).

    PubMed  CAS  Google Scholar 

  4. Cadman E, Heimer R, Davis L: Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism.Science 205, 1135 (1979).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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. 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).

    PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

  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).

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    PubMed  CAS  Google Scholar 

  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).

    PubMed  CAS  Google Scholar 

  18. Mattern J, Jaeger S, Wayss K, Volm M: Therapeutic response of human lung tumour xenografts to cyclophosphamide.Anticancer Res 2, 355 (1982).

    PubMed  CAS  Google Scholar 

  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).

  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. Kufe D W, Egan E M: Enhancement of 5-fluorouracil incorporation into human lymphoblast ribonucleic acid.Biochem Pharmacol 30, 129 (1981).

    Article  PubMed  CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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).

    Article  PubMed  CAS  Google Scholar 

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Wayss, K., Herrmann, R., Mattern, J. et al. Sequential methotrexate (MTX) and 5-fluorouracil (FU) in human tumor xenografts. Med. Oncol. & Tumor Pharmacother. 2, 27–32 (1985). https://doi.org/10.1007/BF02934777

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