Clinical Experience with L-Asparaginase

  • P. P. Carbone
  • C. M. Haskell
  • Brigid G. Leventhal
  • J. B. Block
  • O. S. Selawry
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 33)

Abstract

The administration of L-asparaginase has resulted in reports of beneficial effects in patients with acute leukemia [1–5]. The initial clinical and laboratory studies indicated that L-asparaginase selectively inhibits cancer cells dependent on the nonessential amino acid L-asparagine and offered the promise that L-asparaginase would not be harmful to normal cells. However, later clinical reports dispelled hope for a broad spectrum antitumor effect and also revealed unexpected forms of toxicity [1–7]. Evaluation of the several clinical studies indicates that while the antitumor responses are unique and reproduceable in acute lymphocytic leukemia of children, toxicities are often not consistent in one report compared to another. These differences might be attributable to problems in preparing large quantities of a bacterial protein, and the inclusion of contaminants like endotoxin. In addition it is now possible to obtain L-asparaginase from other species [8] as well as in crystalline form [9] although no major studies have been reported with these preparations. Thus one can only evaluate the relative merits and toxicities of specific preparations, because no comparative clinical trials of the various materials are available.

Keywords

Toxicity Lymphoma Leukemia Pancreatitis Sarcoma 

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References

  1. 1.
    Hill, J. M., Roberts, J., Loeb, E., Khan, A., MacLellan, A., Hill, R. W.: L-asparaginase therapy for leukemia and other malignant neoplasms. J. Amer. med. Ass. 202, 882–888 (1967).CrossRefGoogle Scholar
  2. 2.
    Oettgen, H. F., Old, L. J., Boyse, E. A., Campbell, H. A., Philips, F. S., Clarkson, B. D., Tallal, L., Lepper, R. D., Schwartz, M. K., Kim, J. H.: Inhibition of leukemias in man by L-asparaginase. Cancer Res. 27, 2619–2631 (1967).PubMedGoogle Scholar
  3. 3.
    Old, L. J., Boyse, E. A., Campbell, H. A., Philips, F. S., Clarkson, B. D., Tallal, L., Lepper, R. D., Schwartz, M. K., Kim, J. H. — Schulten, H. K.: Hemmung maligner Neoplasien des Menschen durch L-asparaginase. Klin. Wschr. 47, 65–71 (1969).PubMedCrossRefGoogle Scholar
  4. 4.
    Mathé, G., Amiel, J. L., Schwarzenberg, L., Schneider, M., Cattan, A., Schlumberger, J. R., Hatat, M., De Vassal, F., Jasmin, C., Rosenfeld, C.: Essai de traitement de la leucemie aigue lymphoblastique par la L-asparaginase. Presse méd. 77, 461–463 (1969).PubMedGoogle Scholar
  5. 5.
    Hill, J. M., Loeb, E., MacLellan, A., Khan, A., Roberts, J., Shields, W. F., Hill, N. O.: Response to highly purified L-asparaginase during therapy of acute leukemia. Cancer Res. 29, 1574–1580 (1969).PubMedGoogle Scholar
  6. 6.
    Haskell, C. M., Canellos, G. P., Leventhal, B. G., Carbone, P. P., Block, J. B., Serpick, A. A., Selawry, O. S.: L-asparaginase: Therapeutic and toxic effects in patients with neoplastic disease. New Engl. J. Med. (in press).Google Scholar
  7. 7.
    Canellos, G. P., Leventhal, B. G., Carbone, P. P., Block, J. B., Serpick, A. A., Selawry, O. S. — — — — Serpick, A. A., Hansen, H. H.: Letter to the editor: L-asparaginase toxicity. Cancer Res. 29, 974–975 (1969).PubMedGoogle Scholar
  8. 8.
    Wade, H. E., Elsworth, R., Herbert, D., Keppie, S., Sargeant, K.: A new L-asparaginase with antitumor activity. Lancet 1968 II, 776–777.CrossRefGoogle Scholar
  9. 9.
    Ho, P. K., Poore, G. A.: Experimental antitumor activity of crystalline L-asparaginase from E. coli. Proc. Amer. Ass. Cancer Res. 10, 39 (1969).Google Scholar
  10. 10.
    Canellos, G. P., Carbone, P. P., Ziegler, J. L.: L-asparaginase and Burkitt’s lymphoma. Lancet 1969 II, 380.CrossRefGoogle Scholar
  11. 11.
    Leventhal, B. G., Skeel, R. T., Yankee, R. A., Henderson, E. S.: L-asparaginase and azaserine in acute lymphocytic leukemia. Cancer Chemother. Rep. 54, 47–51 (1970).PubMedGoogle Scholar
  12. 12.
    Schmidt, C. G., Gallmeier, W. M.: Zur enzymtherapie der leukamien. Dtsch. med. Wschr. 93, 2299–2309 (1968).PubMedCrossRefGoogle Scholar
  13. 13.
    Tallal, L., Tan, C., Oettgen, H., McCarthy, M., Helson, L., Murphy, L.: L-asparaginase in 111 children with leukemias and solid tumors. Proc. Amer. Ass. Cancer Res. 10, 92 (1969).Google Scholar
  14. 14.
    Lipton, A., Viola, M., Tauro, G., Gee, T., Krakoff, I., Clarkson, B.: Treatment of leukemias and lymphomas in adults with E. coli L-asparaginase. Program of the 5th Annual Meeting of the Amer. Soc. of Clinical Oncology, San Francisco (Abstract No 23), March 22, 1969.Google Scholar
  15. 15.
    James Holland: Personal communication.Google Scholar
  16. 16.
    Emil Frei, III: Personal communication.Google Scholar
  17. 17.
    Ohnuma, T., Holland, J. F., Freeman, A., Sinks, L.: Studies of asparaginase and asparagine in acute leukemia. Proc. Amer. Ass. Cancer Res. 10, 66 (1969).Google Scholar
  18. 18.
    Patterson, M. K., Jr., Orr, G. R.: Asparagine biosynthesis by the nivokoff hepatoma. Isolation, purification, property and mechanism studies of the enzyme system. J. biol. Chem. 243, 376–380 (1968).PubMedGoogle Scholar
  19. 19.
    Broome, J. D.: Studies on the mechanism of tumor inhibition by L-asparaginase. J. exp. Med. 127, 1055–1072 (1968).PubMedCrossRefGoogle Scholar
  20. 20.
    Horowitz, B., Madras, B. K., Meister, A., Old, L. J., Boyse, E. A., Stockert, E.: Asparagine synthetase activity of mouse leukemias. Science 160, 533–535 (1968).PubMedCrossRefGoogle Scholar
  21. 21.
    Prager, M. D., Backynsky, N.: Asparagine synthetase in normal and malignant tissues; correlation with tumor sensitivity to asparaginase. Arch. Biochem. 127, 645–654 (1968).PubMedCrossRefGoogle Scholar
  22. 22.
    Haskell, C. M., Canellos, G. P.: L-asparaginase resistance in human leukemia: Asparagine synthetase. Biochem. Pharmacol. (in press).Google Scholar
  23. 23.
    Mashburn, L. T.: The effect of combined therapy with L-asparaginase on P1798 lymphosarcoma. Proc. Amer. Ass. Cancer Res. 9, 45 (1968).Google Scholar
  24. 24.
    Jacobs, S. P., Wodinsky, I., Kensler, C. J., Venditti, J.: Therapy of experimental leukemias with combination of L-asparaginase and glutamine antagonists. Proc. Amer. Ass. Cancer Res. 10, 43 (1969).Google Scholar
  25. 25.
    Tarnowski, G. S., Mountain, I. M., Stock, C. C.: Combination therapy of animal tumors with L-asparaginase and glutamine antagonists. Proc. Amer. Ass. Cancer Res. 10, 92 (1969).Google Scholar

Copyright information

© Springer-Verlag Berlin • Heidelberg 1970

Authors and Affiliations

  • P. P. Carbone
    • 1
  • C. M. Haskell
    • 1
  • Brigid G. Leventhal
    • 1
  • J. B. Block
    • 2
  • O. S. Selawry
    • 1
  1. 1.Medicine BranchNational Cancer Institute, National Institutes of HealthBethesdaUSA
  2. 2.Baltimore Cancer Research CenterNational Cancer Institute, National Institutes of HealthBaltimoreUSA

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