Advertisement

Klinische Wochenschrift

, Volume 50, Issue 18, pp 866–870 | Cite as

Wirkung von Dauno-Rubidomycin und Adriamycin auf Enzyme der DNS-Synthese in Leukocyten in vivo und in der Kultur

  • K. Wilms
  • W. Wilmanns
Originalien

Zusammenfassung

Unter der Therapie mit Dauno-Rubidomycin oder Adriamycin wird in der aus dem peripheren Blut isolierten leukämischen Zellpopulation ein Aktivitätsabfall der Enzyme DNS-Polymerase und Thymidinkinase beobachtet. In den ersten Stunden nach Injektion der Anthracyclin-Antibiotica kommt es jedoch regelmäßig zu einem ausgeprägten initialen Anstieg der Aktivität.

Dieses charakteristische Verhalten ließ sich auch in der mit Phytohämagglutinin stimulierten Lymphocytenkultur gesunder Spender reproduzieren, wenn den Kulturen im Maximum der DNS-Synthese eines der Anthracyclin-Antibiotica zugesetzt wurde. Die DNS- und RNS-Synthese war zum Zeitpunkt des Aktivitätsanstieges der genannten Enzyme schon deutlich gehemmt. Durch Hemmversuche mit Inhibitoren der Proteinsynthese konnte wahrscheinlich gemacht werden, daß der Aktivitätsanstieg auf einer Neusynthese von Enzymprotein beruht.

Die Reaktion der DNS-Polymerase wird durch Zugabe von Dauno-Rubidomycin oder Adriamycin zum Inkubationsansatz gehemmt. Diese Hemmung war durch Zugabe weiterer „primer“-DNS zum Teil reversibel.

Schlüsselwörter

Anthracyclin-Antibiotica Akute Leukosen DNS-Polymerase Thymidinkinase PHA-stimulierte Lymphocytenkulturen 

Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture

Summary

The enzyme activities of DNA polymerase and thymidine kinase were determined in peripheral leukemic leukocytes of patients with acute leukemia treated with Dauno-Rubidomycin or Adriamycin. During the first hours after the injection of each drug both enzymes are significantly augmented. After a few days there is a distinct decrease of the enzyme activities preceding the fall of the leukocyte count.

The initial increase in enzyme activity could be reproduced in PHA stimulated lymphocyte cultures of healthy donors by incubating the cells with the Anthracycline antibiotics. During this increase of DNA polymerase and thymidine kinase DNA and RNA synthesis are markedly inhibited. Experiments with inhibitors of protein synthesis make it likely that the remarkable rise in enzyme activity is caused by the synthesis of new enzyme molecules.

The DNA polymerase reaction is inhibited by Dauno-Rubidomycin or Adriamycin. To some extent this could be reversed by the addition of new primer-DNA.

Key words

Anthracycline antibiotics Acute leukemia DNA polymerase Thymidine kinase PHA-stimulated lymphocyte cultures 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Astaldi, G., Eridani, S., Ponti, G. B., Valentini, R., Giangrande, A.: Influence of antiblastic agents applied either in vivo or in vitro on human lymphocyte transformation in cell culture. Blut19, 8 (1969).Google Scholar
  2. 2.
    Bernard, J., Jacquillat, C.: La Rubidomycine. Nouv. Rev. franc. Hémat.7, 317 (1967).Google Scholar
  3. 3.
    Bonadonna, G., Monfardini, S., DeLena, M., Fossati-Bellani, F.: Clinical evaluation of Adriamycin, a new antitumor antibiotic. Brit. med. J.1969, 3, 503.Google Scholar
  4. 4.
    Bonadonna, G., Monfardini, S., DeLena, M., Fossati-Bellani, F., Beretta, G.: Phase I and preliminary phase II evaluation of Adriamycin. Cancer Res.30, 2572 (1970).Google Scholar
  5. 5.
    Bornstein, R. S., Theologides, A., Kennedy, B. J.: Daunorubicin in acute myelogeneous leukemia in adults. J. Amer. med. Ass.207 1301 (1969).Google Scholar
  6. 6.
    Bremerskov, V., Linnemann, R.: Some effects of Daunomycin on the nucleic acid synthesis in synchronized L-cells. Europ. J. Cancer5, 317 (1969).Google Scholar
  7. 7.
    Calendi, E., DiMarco, A., Reggiani, M., Scarpinato, B., Valentini, L.: On physico-chemical interactions between Daunomycin and nucleic acids. Biochim. biophys. Acta (Amst.)103, 25 (1965).Google Scholar
  8. 8.
    Cohen, A., Harley, E. H., Rees, K. R.: Antiviral effect of Daunomycin. Nature (Lond.)222, 36 (1969).Google Scholar
  9. 9.
    DiMarco, A., Gaetani, M., Scarpinato, B.: Adriamycin, a new antibiotic with antitumor activity. Cancer Chemother. Rept.53, 33 (1969).Google Scholar
  10. 10.
    Gado, I., Boromissza, E., Horvath, I.: The effect of Daunomycin on phage induction. J. Antibiot. (Tokyo)22, 574 (1969).Google Scholar
  11. 11.
    Jones, B.: Daunomycin in the treatment of resistant acute lymphoblastic leukemia. Blood30, 890 (1967).Google Scholar
  12. 12.
    Kersten, W.: Interaction of different classes of antibiotics with nucleic acids. Hoppe-Seylers Z. physiol. Chem.349, 956 (1968).Google Scholar
  13. 13.
    Kersten, W., Kersten, H., Szybalski, W.: Physico-chemical properties of complexes between deoxyribonucleic acid and antibiotics which affect ribonucleic acid synthesis. Biochemistry,5, 236 (1968).Google Scholar
  14. 14.
    Livingston, R. B., Carter, S. K.: Daunomycin. Chemother. Fact Sheet (National Cancer Inst.) 1970, 1.Google Scholar
  15. 15.
    Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A.: Chromosome preparations of leukocyte cultures from human peripheral blood. Exptl. Cell Res.20, 613 (1960).Google Scholar
  16. 16.
    Pittillo, R. F., Hunt, D. E.: Biologic activity of Daunomycin in microbial systems. Cancer Chemother. Rept.52, 707 (1968).Google Scholar
  17. 17.
    Rusconi, A.: Different binding sites in DNA for Actinomycin and Daunomycin. Biochim. biophys. Acta (Amst.)123, 627 (1966).Google Scholar
  18. 18.
    Rusconi, A., Calendi, E.: Action of Daunomycin on nucleic acid synthesis in HeLa cells. Biochim. biophys. Acta (Amst.)119, 413 (1966).Google Scholar
  19. 19.
    Rusconi, A., DiMarco, A.: Inhibition of nucleic acid synthesis by Daunomycin and its relationship to the uptake of the drug in HeLa cells. Cancer Res.29, 1507 (1969).Google Scholar
  20. 20.
    Simard, R.: Specific nuclear and nucleolar ultrastructural lesions induced by proflavin and similarly acting anti-metabolites in tissue culture. Cancer Res.26, 2316 (1966).Google Scholar
  21. 21.
    Tan, C. L., Tasaka, H., Yu, K. P., Murphy, L., Karnofsky, D.: Daunomycin, an antitumor antibiotic in the treatment of neoplastic disease. Clinical evaluation with specific reference to childhood leukemia. Cancer (Philad.)20, 333 (1967).Google Scholar
  22. 22.
    Theologides, A., Yarbro, J. W., Kennedy, B. J.: Daunomycin inhibition of DNA and RNA synthesis. Cancer (Philad.)21, 16 (1968).Google Scholar
  23. 23.
    Ward, D. C., Reich, E., Goldberg, I. H.: Base specificity in the interaction of polynucleotides with antibiotic drugs. Science149, 1259 (1965).Google Scholar
  24. 24.
    Whang-Peng, J., Leventhal, B. G., Adamson, J. W., Perry, S.: The effect of Daunomycin on human cells in vivo and in vitro. Cancer (Philad.)23, 113 (1969).Google Scholar
  25. 25.
    Wilmanns, W.: Die Thymidin-Kinase in normalen und leukämischen myeloischen Zellen. Klin. Wschr.45, 505 (1967).Google Scholar
  26. 26.
    Wilms, K.: Enzymatische Untersuchungen der DNS-Synthese unter einer zytostatischen Therapie. Intern. Arbeitstagg. Chemo- und Immunotherapie der Leukosen und malignen Lymphome. Wien 1969.Google Scholar
  27. 27.
    Wilms, K., Jaenicke, L.: Desoxyribonucleinsäure-Polymerase in menschlichen Leukozyten. Enzymaktivität bei Leukämien und Virusinfektionen. Klin. Wschr.46, 407 (1968).Google Scholar
  28. 28.
    Wilms, K., Wilmanns, W.: Enzymatischen Untersuchungen der DNS-Synthese in phytohämagglutininstimulierten Lymphocytenkulturen. Klin. Wschr.47, 39 (1969).Google Scholar

Copyright information

© Springer-Verlag 1972

Authors and Affiliations

  • K. Wilms
    • 1
  • W. Wilmanns
    • 1
  1. 1.Med. Univ.-Klinik Tübingen, o. Lehrstuhl und Abt. Innere Medizin IIGermany

Personalised recommendations