Skip to main content
SpringerLink
Log in

Dihydrofolat-Reductase und Thymidin-Kinase im Knochenmark unter der Einwirkung von Folsäureantagonisten

  • Originalien
  • Published:
Klinische Wochenschrift Aims and scope Submit manuscript

Zusammenfassung

Unter der Einwirkung von Folsäureantagonisten werden in Cytolysaten nichtleukämischer Knochenmarkzellen die Enzyme FH2-Reductase und Thymidin-Kinase untersucht. Es wird gezeigt, daß die proliferierenden Zellen über folgende Möglichkeiten zur Kompensation des Hemmeffektes der Folsäureantagonisten auf die DNS-Synthese verfügen:

  1. 1.

    Anstieg der Thymidin-Kinase im Stadium der FH2-Reductase-Blockierung;

  2. 2.

    Neubildung von FH2-Reductase.

Die wechselseitigen Beziehungen zwischen Thyminmethylgruppen-de novo-Synthese und Verwertung von vorgebildetem Thymidin für die Bildung der DNS werden diskutiert. Die beschriebenen Untersuchungen ermöglichen eine prognostische Beurteilung cytotoxischer Nebenwirkungen, die unter der Behandlung mit Folsäureantagonisten auf die normale Zellproliferation auftreten können.

Summary

The enzymes FH2-reductase and thymidine kinase are investigated in cytolysates of non leucemic bone marrow cells under the influence of folic acid antagonists. The following mechanisms for compensation the inhibitory action of folic acid antagonists are demonstrated in proliferating cells:

  1. 1.

    Increase of thymidine kinase activity when FH2-reductase is blocked;

  2. 2.

    formation of new FH2=reductase.

Relations between de novo synthesis of thymine methylgroups and utilisation of preformed thymidine for DNA-synthesis are discussed. The metabolic investigations described offer a helpful technique for prognosis of possible toxic side effects on normal cell proliferation under treatment with folic acid antagonists.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Literatur

  1. Aranow, I.: Studies on drug resistance in mammalian cells. I. Amethopterin resistance in mouse fibroblasts. J. Pharmacol. exp. Ther.127, 116–121 (1959).

    Google Scholar 

  2. Bertino, J. R.: The mechanism of action of folate antagonists in man. Cancer Res.23, 1286–1306 (1963).

    Google Scholar 

  3. Bertino, J. R., D. M. Donohue, B. Simmons, B. W. Gabrio, R. Silber, andF. M. Huennekens: The “induction” of dihydrofolic reductase activity in leucocytes and erythrocytes of patients treated with amethopterin. J. clin. Invest.42, 466–475 (1962).

    Google Scholar 

  4. Bianchi, P. A., J. A. V. Butler, A. R. Crathorn, andK. V. Shooter: The thymidine phosphorylating kinase. Biochim. biophys. Acta (Amst.)53, 123–131 (1961).

    Google Scholar 

  5. Blakeley, R. L.: Cristalline dihydropteroylglutamic acid. Nature (Paris)40, 1684 (1961).

    Google Scholar 

  6. Bock, H. E.: Das Hämomyelogramm. Klin. Wschr.18, 1565–1568 (1939).

    Google Scholar 

  7. Breitman, T. R.: The feed back inhibition of thymidine kinase. Biochim. biophys. Acta (Amst.)67, 153–155 (1963).

    Google Scholar 

  8. Bresnick, E., andR. J. Karjala: End-product inhibition of thymidine kinase activity in normal and leucemic leucocytes. Cancer Res.24, 841–846 (1964).

    Google Scholar 

  9. Broquist, H. P., E. L. R. Stokstad, andT. H. Jukes: Some biological and chemical properties of the citrovorum factor. Fed. Proc.9, 156 (1950).

    Google Scholar 

  10. Burchenal, J. H., andG. M. Babcock: Prevention of toxicity of massive doses of amethopterin by citrovorum factor. Proc. Soc. exp. Biol. (N. Y.)76, 382–384 (1951).

    Google Scholar 

  11. Burchenal, J. H., M. L. Murphy, R. R. Ellison, M. P. Sykes, T. C. Tau, L. A. Leone, D. A. Karnofsky, L. F. Carver, H. W. Dargeou, andC. P. Rhoads: Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leucemia and allied diseases. Blood8, 965–999 (1953).

    Google Scholar 

  12. Condit, P. T., I. Shnider, andA. H. Owens jr.: Studies on the folic acid vitamins. VIII. The effects of large doses of amethopterin in patients with cancer. Cancer Res.22, 706–712 (1962).

    Google Scholar 

  13. Bläker, F., K. Fischer u.G. Landbeck: Quantitative Analysen der Immunoglobuline (IgA, IgG, IgM) während cytostatischer Behandlung. Dtsch. med. Wschr.50, 2259–2262 (1966).

    Google Scholar 

  14. Futterman, S.: Enzymatic reduction of folic acid and dihydrofolic acid to tetrahydrofolic acid. J. biol. Chem.228, 1031–1038 (1957).

    Google Scholar 

  15. Goldin, A., J. M. Venditti, J. Kline, andN. Mantel: Evadication of leucemic cells (L 1210) by methotrexate and methotrexate plus citrovorum factor. Nature (Lond.)212, 1548–1558 (1966).

    Google Scholar 

  16. Greening, W. P.: Methotrexate in the treatment of advanced cancer of the brest. In: Methotrexate in the treatment of cancer, p. 29–33. Bristol: J. Wright & Sons 1962.

    Google Scholar 

  17. Hakala, M. T., S. F. Zakrzewski, andC. A. Nichol: Relation of folic acid reductase to amethopterin resistance in cultured mammalian cells. J. biol. Chem.236, 952–958 (1961).

    Google Scholar 

  18. Holland, J. F.: Folic acid antagonists. Clin. Pharmacol. Ther.3, 374–409 (1961).

    Google Scholar 

  19. Ives, D. H., P. A. Morse, andV. R. Potter: Feed back inhibition of thymidine kinase by thymidine triphosphate. J. biol. Chem.238, 1467–1474 (1963).

    Google Scholar 

  20. Li, M. C., R. Hertz, andD. M. Bergenstal: Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. New Engl. J. Med.259, 66–74 (1958).

    Google Scholar 

  21. Marsh, I., andS. Perry: Thymidine catabolism by normal and leucemic human leucocytes. J. clin. Invest.43, 267–278 (1964).

    Google Scholar 

  22. Miescher, P. A., andD. Riethmüller: Diagnosis and treatment of systemic lupus erythematodes. Seminars in Hemat.2, 1–28 (1965).

    Google Scholar 

  23. Misra, D. K., S. P. Humphreys, M. Friedkin, A. Goldin, andE. J. Crawford: Increased dihydrofolic reductase activity as a possible basis of drug resistance in leucemia. Nature (Lond.)189, 39–42 (1961).

    Google Scholar 

  24. Morse, P. A., andA. V. Potter: Pyrimidine metabolism in tissue culture cells derived from rat hepatomes. I. Suspension cell cultures derived from the Novikoff hepatoma. Cancer Res.25, 499–508 (1965).

    Google Scholar 

  25. Nieth, H., u.J. Gayer: Vorwiegend renale und anämische Verlaufsform eines Lupus erythematodes disseminatus. Med. Welt 455–456 (1965).

  26. Peters, J. M., andD. M. Greenberg: Dihydrofolic acid reductase. J. Amer. chem. Soc.80, 6679–6682 (1958).

    Google Scholar 

  27. Potter, R. L., andO. F. Nyagaard: The conversion of thymidine to thymine nucleotides and desoxyribonucleic acid in vivo. J. biol. Chem.238, 2150–2155 (1963).

    Google Scholar 

  28. Rubini, J. R.: In vitro DNA Labeling of bone marrow and leucemic blood leucocytes with tritiated thymidine. II. H3 thymidine biochemistry in vitro. J. Lab. clin. Med.68, 566–576 (1966).

    Google Scholar 

  29. Schoenbach, E. B., E. M. Greenspan, andJ. Colsky: Reversal of aminopterin and amethopterin toxicity by citrovorum factor. J. Amer. med. Ass.144, 1558–1560 (1950).

    Google Scholar 

  30. Vanscott, E. J., R. Auerbach, andG. D. Weinstein: Parenteral methotrexate in psoriasis. Arch. Derm.89, 550 (1964).

    Google Scholar 

  31. Silber, R., B. W. Gabrio, andF. M. Huennekens: Studies on normal and leucemic leucocytes. VI. Thymidylate synthetase and deoxycytidylate deaminase. J. clin. Invest.42, 1913–1921 (1963).

    Google Scholar 

  32. Sullivan, R. D.: The dose, duration and route of administration studies of methotrexate in clinical cancer chemotherapy. In: Methotrexate in the treatment of cancer, p. 50–55. Bristol:Wright & Sons 1962.

    Google Scholar 

  33. Weissman, S. M., R. M. S. Smellie, andJ. Paul: Studies on the biosynthesis of desoxyribonucleic acid by extracts of mammalian cells. IV. The phosphorylation of thymidine. Biochim. biophys. Acta (Amst.)45, 101–110 (1960).

    Google Scholar 

  34. Wells, W., andR. J. Winzler: Metabolism of human leucocytes in vitro. III. Incorporation of formate-C14 into cellular components of leucemic human leucocytes. Cancer Res.19, 1086–1090 (1959).

    Google Scholar 

  35. Werkheiser, W. C.: Specific binding of 4-amino-folic acid analogues by folic acid reductase. J. biol. Chem.236, 888–893 (1961).

    Google Scholar 

  36. Werkheiser, W. C.: The biochemical, cellular and pharmacological action and effects of the folic acid antagonists. Cancer Res.23, 1277–1286 (1963).

    Google Scholar 

  37. Werkheiser, W. C., S. F. Zakrzewski, andC. A. Nichol: Assay for 4-amino folic acid analogues by inhibition of folic acid reductase. J. Pharmacol. exp. Ther.317, 162–167 (1962).

    Google Scholar 

  38. Wilmanns, W.: Bestimmung, Eigenschaften und Bedeutung der Dihydrofolsäure-Reduktase in den weißen Blutzellen bei Leukämien. Klin. Wschr.40, 533–540 (1962).

    Google Scholar 

  39. Wilmanns, W.: Der Stoffwechsel der Einkohlenstoffcinheiten in den unreifen Vorstufen normaler Leukozyten. Med. Welt52, 2667–2670 (1963).

    Google Scholar 

  40. Wilmanns, W.: Der Wirkungsmechanismus von Folsäureantagonisten bei der Leukämiebehandlung. Xth Congr. of the Internat. Soc. of Haemat. A 21 Stockholm 1964.

  41. Wilmanns, W.: The action of folic acid antagonists on enzymes of thyminenucleotide synthesis in the myeloproliferative system. XIth Congr. of the Internat. Soc. of Haemat. Syndney 1966, p. 343.

  42. Wilmanns, W.: Die Thymidin-Kinsae in normalen und leukämischen myeloischen Zellen. Klin. Wschr.45, 505–511 (1967).

    Google Scholar 

  43. Wilmanns, W., u.L. Jaenicke: Die Bedeutung des Folsäurestoffwechsels für die normale und pathologische Reifung von Blutzellen. Klin. Wschr.41, 1077–1082 (1963).

    Google Scholar 

  44. Winzler, R. J., W. Wells, J. Shapira, A. D. Williams, I. Bornstein, M. J. Burr, andW. R. Best: Metabolism of human leukocytes in vitro. II. The effects of several agents on the incorporation of radioactive formate and glycine. Cancer Res.19, 377–388 (1959).

    Google Scholar 

  45. Zakrzewski, S. F.: Purification and properties of folic reductase from chicken liver. J. biol. Chem.235, 1776–1780 (1960).

    Google Scholar 

  46. Zakrzewski, S. F.: The mechanism of binding of folate analogues by folate reductase. J. biol. Chem.238, 1485–1490 (1963).

    Google Scholar 

  47. Zakrzewski, S. F., andC. A. Nichol: On the enzymic reduction of folic acid by a purified hydrogenase. Biochim. biophys. Acta (Amst.)27, 425–426 (1958).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Universitätsklinik Tübingen, Germany

    W. Wilmanns

Authors
  1. W. Wilmanns
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Mit Unterstützung der Deutschen Forschungsgemeinschaft.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilmanns, W. Dihydrofolat-Reductase und Thymidin-Kinase im Knochenmark unter der Einwirkung von Folsäureantagonisten. Klin Wochenschr 45, 987–994 (1967). https://doi.org/10.1007/BF01746131

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01746131

Search

Navigation