Regulation of Thymidylate Synthase in Human Colon Cancer Cells Treated with 5-Fluorouracil and Interferon-Gamma

  • Edward Chu
  • Carmen J. Allegra
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 339)

Abstract

5-Fluorouracil (5-FU) remains, at present, the single most active agent for the treatment of human colorectal cancer. When used as a single agent against advanced disease, it is associated with an overall response rate of only 15–20%, and therapy with 5-FU is unable to prolong the survival of treated patients [1–3]. Since few other agents have been identified for the treatment of human colorectal cancer, considerable attention has focused on elucidating the basic mechanisms of 5-FU action. The cytotoxic effects of 5-FU have been traditionally ascribed either to inhibition of the critical target enzyme thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) with subsequent inhibition of thymidylate and DNA biosynthesis, to incorporation of the 5-FU metabolite 5-fluorouridine-5′-triphosphate (FUTP) into RNA with resultant inhibition of RNA synthesis and function, or to incorporation of the 5-FU metabolite 5-fluoro-2′-deoxyuridine-5′-triphosphate (FdUTP) into DNA with resultant inhibition of DNA synthesis and function [1–11]. The relative contribution of each of these metabolic processes remains unclear at this time.

Keywords

H630 Cell Human Colorectal Cancer Dialyze Fetal Bovine Serum Fluorinated Pyrimidine Human Ovarian Cancer Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    H.M. Pinedo and G.F.J. Peters, Fluorouracil: biochemistry and pharmacology, J. Clin. Oncol. 6: 1653–1664 (1988).PubMedGoogle Scholar
  2. 2.
    C. Heidelberger, Fluorinated pyrimidines and their nucleosides, in: “Antineoplastic and Immunosuppressive Agents,” A. Sartorelli and D. Johns, eds, Springer-Verlag, New York, pp 193–231 (1975).Google Scholar
  3. 3.
    C. Heidelberger, P.V. Danenberg and R.G. Moran, Fluorinated pyrimidines and their nucleosides, Adv. Enzymol. Related Areas Mol. Biol. 54: 57–119 (1989).Google Scholar
  4. 4.
    D.V. Santi, C.S. McHenry and H. Sommer, Mechanism of interaction of thymidine synthetase with 5-fluorodeoxyuridylate, Biochemistry 13: 471–481 (1974).PubMedCrossRefGoogle Scholar
  5. 5.
    B. Ardalan, D. Cooney, H. Jayaram, C. Carrico, R. Glazar, J. Macdonald and P.S. Schein, Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil, Cancer Res. 40: 1431–1437 (1980).PubMedGoogle Scholar
  6. 6.
    S. Spiegelman, R. Sawyer, R. Nayak, E. Ritzi, R. Stolfi and D. Martin, Improving the antitumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation, Proc. Natl. Acad. Sci. USA 77: 4966–4970 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    D.S. Wilkinson and J. Crumley, The mechanism of 5-fluorouridine toxicity in Novikoff hepatoma cells, Cancer Res. 36: 4032–4038 (1976).PubMedGoogle Scholar
  8. 8.
    R.I. Glazar and A.L. Peale, The effect of 5-fluorouracil on the synthesis of nuclear RNA in L1210 cells in vitro, Mol. Pharmacol. 16: 270–277 (1979).Google Scholar
  9. 9.
    D.W. Kufe, P.P. Major, E.M. Egan and E. Loh, 5-Fluoro-2′-deoxyuridine incorporation in L1210 DNA, J. Biol. Chem. 256: 8885–8888 (1981).PubMedGoogle Scholar
  10. 10.
    P.P. Major, E. Egan, D. Herrick and D.W. Kufe, 5-Fluorouracil incorporation in DNA of human breast carcinoma cells, Cancer Res. 42: 3005–3009 (1982).PubMedGoogle Scholar
  11. 11.
    Y-C. Cheng and K. Nakayama, Effects of 5-fluoro-2′-deoxyuridine on DNA metabolism in HeLa cells, Mol. Pharmacol. 23: 171–174 (1983).CrossRefGoogle Scholar
  12. 12.
    D. Kessel, T.C. Hall and I. Wodinsky, Nucleotide formation as a determinant of 5-fluorouracil response in mouse leukemia, Science 154: 911–913 (1966).PubMedGoogle Scholar
  13. 13.
    J.A. Houghton, S.J. Maroda, J.O. Phillips and P.J. Houghton, Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice, Cancer Res. 41: 144–149 (1981).PubMedGoogle Scholar
  14. 14.
    M.A. Mulkins and C. Heidelberger, Biochemical characterization of fluoropyrimidine-resistant murine leukemic cell lines, Cancer Res. 42: 965–973 (1982).PubMedGoogle Scholar
  15. 15.
    M.B. Yin, S.F. Zakrzewski and M.T. Hakala, Relationship of cellular folate cofactor pools to the activity of 5-fluorouracil, Mol. Pharmacol. 23: 190–197 (1983).Google Scholar
  16. 16.
    D.J. Fernandes and S.K. Crawford, Resistance of CCRF-CEM cloned sublines to 5-fluorodeoxyuridine associated with enhanced phosphatase activities, Biochem. Pharmacol. 34: 125–132 (1985).Google Scholar
  17. 17.
    S.H. Berger, C-H. Jenh, L.F. Johnson and F. Berger, Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells, Mol. Pharmacol. 28: 461–467 (1985).Google Scholar
  18. 18.
    J.L. Clark, S.H. Berger, A. Mittelman and F. Berger, Thymidylate synthase gene amplification in a colon tumor resistant to fluoro-pyrimidine chemotherapy, Cancer Treat. Rep. 71: 261–265 (1987).Google Scholar
  19. 19.
    S.H. Berger, K.W. Barbour and F. Berger, A naturally occurring variation in thymidylate synthase structure is associated with a reduced response to 5-fluoro-2′-deoxyuridine in a human colon tumor cell line, Mol. Pharmacol. 34: 480–484 (1988).Google Scholar
  20. 20.
    E. Chu, G-M. Lai, S. Zinn and C.J. Allegra, Resistance of a human ovarian cancer line to 5-fluorouracil associated with decreased levels of 5-fluorouracil in DNA, Mol. Pharmacol. 38: 410–417 (1990).Google Scholar
  21. 21.
    E. Chu, J.C. Drake, D.M. Koeller, S. Zinn, C.A. Jamis-Dow, G.C. Yeh and C.J. Allegra, Induction of thymidylate synthase associated with multidrug resistance in human breast and colon cancer cell lines, Mol. Pharmacol. 39: 136–143 (1990).Google Scholar
  22. 22.
    C. Aschele, A. Sobrero, M.A. Faderan and J.R. Bertino, Novel mecha-nism(s) of resistance to two different clinically relevant dose schedules, Cancer Res. 52: 1855–1864 (1992).PubMedGoogle Scholar
  23. 23.
    C.P. Spears, A.H. Shahinian, R.G. Moran, C. Heidelberger and T.H. Corbett, In vivo kinetics of thymidylate synthase inhibition in 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas, Cancer Res. 42: 450–456 (1982).PubMedGoogle Scholar
  24. 24.
    W.L. Washtien, Increased levels of thymidylate synthetase in cells exposed to 5-fluorouracil, Mol. Pharmacol. 25: 171–177 (1984).Google Scholar
  25. 25.
    M. Berne, B. Gustavsson, O. Almersjo, P.C. Spears and R. Frosing, Sequential methotrexate/5-FU: FdUMP formation and TS inhibition in a transplantable rodent colon adenocarcinoma, Cancer Chemother. Pharmacol. 16: 237–242 (1986).Google Scholar
  26. 26.
    M. Berne, B. Gustavsson, O. Almersjo, C.P. Spears and J. Waldenstrom, Concurrent allopurinol and 5-fluorouracil: 5-fluoro-2′-deoxyuri-dylate formation and thymidylate synthase inhibition in rat colon carcinoma and in regenerating rat liver, Cancer Chemother. Pharmacol. 20: 193–197 (1987).Google Scholar
  27. 27.
    K. Keyomarsi and R.G. Moran, Mechanism of the cytotoxic synergism of fluoropyrimidines and folinic acid in mouse leukemic cells, J. Biol. Chem. 263: 14402–14409 (1988).PubMedGoogle Scholar
  28. 28.
    S.M. Swain, M.E. Lippman, E.F. Egan, J.C. Drake, S.M. Steinberg and C.J. Allegra, Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer, J. Clin. Oncol. 7: 890–899 (1989).PubMedGoogle Scholar
  29. 29.
    M. Namba, T. Miyoshi, T. Kanamori, M. Nobuhara, T. Kimoto and S. Ogawa, Combined effects of 5-fluorouracil and interferon on proliferation of human neoplastic cells in culture, Gann 73: 819–824 (1982).PubMedGoogle Scholar
  30. 30.
    T. Miyoshi, S. Ogawa, T. Kanamori, M. Nobuhara and M. Namba, Interferon potentiates cytotoxic effects of 5-fluorouracil on cell proliferation of established human cell lines originating from neoplastic tissues, Cancer Lett. 17: 239–241 (1983).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Inoue and Y.H. Tan, Enhancement of actinomycin-D and cis-diammine-dichloroplatinum(II)-induced killing of human fibroblasts by human beta interferon, Cancer Res. 43: 5484–5488 (1983).PubMedGoogle Scholar
  32. 32.
    D. Le, Y.K. Yip and J. Vilcek, CYtolytic activity of interferon-gamma and its synergism with 5-fluorouracil, Int. J. Cancer 34: 495–500 (1984).PubMedCrossRefGoogle Scholar
  33. 33.
    S. Yamamoto, H. Tanaka, T. Kanamori, M. Nobuhara and M. Namba, In vitro studies of cytotoxic effects of anticancer drugs by interferon on a human neoplastic cell line (HeLa), Cancer Lett. 20: 131–138 (1983).PubMedCrossRefGoogle Scholar
  34. 34.
    Y. Kimoto, Antitumor effect of interferons with chemotherapeutic agents, Gan. To Kayaku Ryoho 13: 293–301 (1986).Google Scholar
  35. 35.
    K. Gohji, S. Macda, T. Sugiyama, J. Ishigumi and S. Kamidona, Enhanced inhibition of anticancer drugs by human recombinant gamma-interferon for human renal cell carcinoma in vitro, J. Urol. 137: 539–543 (1987).PubMedGoogle Scholar
  36. 36.
    M.S. Mitchell, Combining chemotherapy with biological response modifiers in treatment of cancer, J. Natl. Cancer Inst. 80: 1445–1450 (1988).PubMedCrossRefGoogle Scholar
  37. 37.
    L. Elias and H.A. Crissman, Interferon effects on the adenocarcinoma 38 and HL-60 cell lines: antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites, Cancer Res. 48: 4868–4873 (1988).PubMedGoogle Scholar
  38. 38.
    L. Elias and J.M. Sandoval, Interferon effects upon fluorouracil metabolism by HL-60 cells, Biochem. Biophys. Res. Commun. 130: 379–388 (1989).Google Scholar
  39. 39.
    E.L. Schwartz, M. Hoffman, C.J. O’Connor and S. Wadler, Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells, Biochem. Biophys. Res. Commun. 182: 1232–1239 (1992).CrossRefGoogle Scholar
  40. 40.
    J.A. Houghton, D.A. Adkins, A. Rahman and P.J. Houghton, Interaction between 5-fluorouracil, [6RS]leucovorin, and recombinant human interferon-alpha-2a in cultured colon adenocarcinoma cells, Cancer Commun. 3: 225–231 (1991).PubMedGoogle Scholar
  41. 41.
    E. Chu, S. Zinn, D. Boarman and C.J. Allegra, Interaction of gamma interferon and 5-fluorouracil in the H630 human colon carcinoma cell line, Cancer Res. 50: 5834–4840 (1990).PubMedGoogle Scholar
  42. 42.
    P. Chomczynski and N. Sacchi, Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction, Anal. Biochem. 162: 156–159 (1987).Google Scholar
  43. 43.
    J. Harford, An artifact explains the apparent association of the transferrin receptor with a ras gene product, Nature 311: 493–495 (1984).CrossRefGoogle Scholar
  44. 44.
    U.K. Laemmli, Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature 227: 680–685 (1986).CrossRefGoogle Scholar
  45. 45.
    M. Bradford, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Anal. Biochem. 72: 248–254 (1976).PubMedCrossRefGoogle Scholar
  46. 46.
    E. Chu, D.M. Koeller, J.L. Casey, J.C. Drake, B.A. Chabner, P.G. Elwood, S. Zinn and C.J. Allegra, Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase, Proc. Natl. Acad. Sci. USA 88: 8977–8981 (1991).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Edward Chu
    • 1
  • Carmen J. Allegra
    • 1
  1. 1.NCI-Navy Medical Oncology BranchNational Cancer Institute,NIHNMOB 8/5101-Naval HospitalBethesdaUSA

Personalised recommendations