Experientia

, Volume 52, Issue 1, pp 5–13 | Cite as

The history of cyclosporin A (Sandimmune®) revisited: Another point of view

  • H. F. Stähelin

Abstract

The immunosuppressant cyclosporin A (Sandimmune®) has become the first line treatment for preventing rejection of transplanted organs and for certain, autoimmune diseases. The discovery of that drug and its preclinical development are described, and it is shown that most earlier accounts of the history of this compound are, in important respects, incorrect and misleading.

Key words

Cyclosporin A Sandimmune® ovalicin cytochalasin fungus metabolites history discovery 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Aldridge, D. C., Armstrong, J. J., Speake, R. N., and Turner, W. B., The cytochalasins, a new class of biologically active mould metabolites. Chem. Commun. (1967) 26–27.Google Scholar
  2. 2.
    Arrenbrecht, S., and Lazary, S., Effect of the immunosuppressive agent ovalicin on the kinetics of antibody formation. Agents and Actions1 (1970) 221–226.PubMedGoogle Scholar
  3. 3.
    Bäumler, E.: Die grossen Medikamente. Lübbe, Bergisch Gladbach 1992.Google Scholar
  4. 4.
    Bernard, J., Ciclosporin: Foreword. Prog. Allergy38 (1986) 1–8.Google Scholar
  5. 5.
    Bollinger, P., Sigg, H. P., and Weber, H. P., Die Struktur von Ovalicin. Hely. chim. Acta56 (1973) 819–830.Google Scholar
  6. 6.
    Borel, J. F., Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology31 (1976) 631–641.PubMedGoogle Scholar
  7. 7.
    Borel, J. F., The history of cyclosporin A and its significance, in: Cyclosporin A, pp. 5–17. Ed. D. J. G. White. Elsevier, Oxford 1982.Google Scholar
  8. 8.
    Borel, J. F., Address at the presentation of the Prix Galien of France, published in Press Folder of Sandoz Basel, May 1984.Google Scholar
  9. 9.
    Borel, J. F., Interview published in the brochure “Sandimmune” of Laboratories Sandoz, France, 1984.Google Scholar
  10. 10.
    Borel, J. F., Feurer, C., Gubler, H. U., and Stähelin, H., Biological effects of cyclosporin A: a new antilymphocytic agent. Agents and Actions6 (1976) 468–475.PubMedGoogle Scholar
  11. 11.
    Borel, J. F., Feurer, C., Magnée, C., and Stähelin, H., Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology32 (1977) 1017–1025.PubMedGoogle Scholar
  12. 12.
    Borel, J. F., Kis, Z. L., The discovery and development of cyclosporine (Sandimmune). Transplant. Proc.23 (1991) 1867–1874.PubMedGoogle Scholar
  13. 13.
    Borel, J. F., Rüegger, A., and Stähelin, H., Cyclosporin A: a new antilymphocytic agent. Experientia32 (1976) 777.Google Scholar
  14. 14.
    Bridel, F., Ces médicaments qui ont changé la vie. Chapitre 3, pp. 26–38. Payot, Lausanne 1985.Google Scholar
  15. 15.
    Bueding, E., Hawkins, J. and Cha, Y.-N., Antischistosomal effects of cyclosporin A. Agents and Actions11 (1981) 380–383.PubMedGoogle Scholar
  16. 16.
    Calne, R. Y., The development of immunosuppression in organ transplantation. Progr. Transplant.1 (1984) 1–10.Google Scholar
  17. 17.
    Calne, R. Y., and White, D. J. G., cyclosporin A — a powerful immunosuppressant in dogs with renal allografts. IRCS med. Sci.5 (1977) 595.Google Scholar
  18. 18.
    Calne, R. Y., White, D. J. G., Rolles, K., Smith, D. P., and Herbertson, B. M., Prolonged survival of pig orthotopic heart grafts treated with cyclosporin A. LancetI (1978) 1183–1185.Google Scholar
  19. 19.
    Calne, R. Y., White, D. J. G., Thiru, S., Evans, D. B., McMaster, P., Dunn, D. C., Craddock, G. N., Pentlow, D. B., and Rolles, K., Cyclosporin A in patients receiving renal allografts from cadaver donors. LancetII (1978) 1323–1327.Google Scholar
  20. 20.
    Carter, S. B., Effects of cytochalasins on mammalian cells. Nature, Lond.213 (1967) 261–264.Google Scholar
  21. 21.
    Closse, A., und Huguenin, R., Isolierung und Strukturaufklärung von Chlamydocin. Helv. chim. Acta57 (1974) 533–545.PubMedGoogle Scholar
  22. 22.
    Dawkins, A. W., Grove, J. F., and Tidd, B. K., Diacetoxyscirpenol and some related compounds. Chem. Commun. (1965) 27–28.Google Scholar
  23. 23.
    DeSimone, P. A., Greco, F. A., Lessner, H. F., and Bartolucci, A., Phase II evaluation of anguidine (NSC 141537) in 5-day courses in colorectal adenocarcinoma. A Southeastern Cancer Study Group trial. Am. J. clin. Oncol.9 (1986) 187–188.PubMedGoogle Scholar
  24. 24.
    Doyle, T. W., and Bradner, W. T., Trichothecanes, in: Anticancer agents based on natural product models, pp. 43–72. Eds J. M. Cassady and J. D. Douros. Academic Press, New York 1980.Google Scholar
  25. 25.
    Dreyfuss, M., Neue Erkenntnisse aus dem pharmakologischen Pilz-Screening. Sydowia39 (1986) 22–36.Google Scholar
  26. 26.
    Dreyfuss, M., and Chapela, I. H., Potential of fungi in the discovery of novel, low-molecular weight pharmaceuticals, in: The Discovery of Natural Products with Therapeutic Potential, pp. 49–80. Ed. V. P. Gullo. Butterworth-Heinemann, Boston 1994.Google Scholar
  27. 27.
    Dreyfuss, M., Härri, E., Hofmann, H., Kobel, H., Pache, W., and Tscherter, H., Cyclosporin A and C. New metabolites fromTrichoderma polysporum (Link ex pers.) Rifai. Europ. J. appl. Microbiol.3 (1976) 125–133.Google Scholar
  28. 28.
    Editorial, Cyclosporin turns five. Science242 (1988) 198.Google Scholar
  29. 29.
    Flury, E., Mauli, R., and Sigg, H. P., The constitution of diacetoxyscirpenol. Chem. Commun. (1965) 26–27.Google Scholar
  30. 30.
    Gorner, P., Wonderworker. Chicago Tribune, Dec. 28, 1988.Google Scholar
  31. 31.
    Green, C. J., and Allison, A. C., Extensive prolongation of rabbit kidney allograft survival after short-term cyclosporin-A treatment. The LancetI (1978) 1182–1183.Google Scholar
  32. 32.
    Gutzwiller, J., and Tamm, C., Ueber die Struktur von Verrucarin A. Helv. chim. Acta48 (1965) 157–176.PubMedGoogle Scholar
  33. 33.
    Haller, M., Der Sandimmun-Krimi: Die Geschichte des Medikamentes, mit dem heute am meisten Geld verdient wird. Weltwoche (Zürich) Dec. 3 (1992) 61–63; Dec. 10 (1992) 53; Dec. 17 (1992) 47. An English translation by F. Niklaus is available from the author of the present paper.Google Scholar
  34. 34.
    Härri, E., Loeffler W., Sigg, H. P. Stähelin, H., Stoll, Ch., Tamm, Ch., and Wiesinger, D., Ueber die Verrucarine und Roridine, eine Gruppe von cytostatisch hochwirksamen Antibiotica aus Myrothecium-Arten. Helv. chim. Acta45 (1962) 839–853.Google Scholar
  35. 35.
    Härri, E., Loeffler W., Sigg, H. P., Stähelin, H., and Tamm, Ch., Ueber die Isolierung neuer Stoffwechselprodukte aus Penicillium brefeldianum Dodge. Helv. chim. Acta46 (1963) 1235–1243.Google Scholar
  36. 36.
    Hartmann, G. R., Richter, H., Weiner, E. M., and Zimmermann, W., On the mechanism of action of the cytostatic drug anguidine and of the immunosuppressive agent ovalicin, two sesquiterpenes from fungi. Planta med.34 (1978) 231–252.PubMedGoogle Scholar
  37. 37.
    Hofmann, A., Planung und Zufall in der pharmazeutischchemisschen Forschung. Sandoz Bulletin50 (1979) 4–17.Google Scholar
  38. 38.
    Kolata, G., Drug transforms transplant medicine (Editorial). Science221 (1983) 40–42.PubMedGoogle Scholar
  39. 39.
    Kostakis, A. J., White, D. J. G., and Calne, R. Y., Prolongation of the rat heart allograft survival by cyclosporin A. IRCS med. Sci.5 (1977) 280.Google Scholar
  40. 40.
    Lazary S., and Stähelin, H., Immunosuppressive, Wirkung von Podophyllumstoffen und andern Cytostatica, in: Proc. 5th Internat. Congr. Chemotherapy, (Vienna), pp. 317–322. Eds K. H. Spitzy and H. Haschek. Wiener mediz. Akademie. Wien 1967.Google Scholar
  41. 41.
    Lazary, S., and Stähelin, H., Immunosuppressive and specific antimitotic effects of ovalicin. Experientia24 (1968) 1171–1173.PubMedGoogle Scholar
  42. 42.
    Lazary, S., and Stähelin, H., Immunosuppressive effect of a new antibiotic: ovalicin. Antibiotica et Chemother.15 (1969) 177–181.Google Scholar
  43. 43.
    Lazary, S., and Stähelin, H., Ovalicin and other drugs in experimental allergic encephalomyelitis (EAE). Experientia26 (1970) 691.Google Scholar
  44. 44.
    Mirocha, C. J., Pawlowsky, R. A., Chatterjee, K., Watson, S., and Hayes, W., Analysis of Fusarium toxins in various samples implicated in biological warfare in Southeast Asia. J. Ass. off. analyt. Chem.66 (1983) 1485–1499.Google Scholar
  45. 45.
    Misumi, Y., Misumi, Y., Miki, K., Takatsuki, A., Tamura, G., and Ikehara, Y., Novel blockade by brefeldin A of intracellular transport of secretory proteins in cultured rat hepatocytes. J. biol. Chem.261 (1986) 11398–11403.PubMedGoogle Scholar
  46. 46.
    Pestka, J. J., and Forsell, J. H., Inhibition of human lymphocyte transformation by the macrocyclic trichothecenes roridin A and verrucarin A. Toxic. Lett.41 (1988) 215–222.Google Scholar
  47. 47.
    Petcher, T. J., Weber, H. P., and Rüegger., A., Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helv. chim. Acta59 (1976) 1480–1488.PubMedGoogle Scholar
  48. 48.
    Powles, R. L., Barrett, A. J., Clink, H., Kay, H. E. M., Sloane, J., and McElwain, T. J., Cyclosporin A for the treatment of graft-versus-host disease in man. LancetII (1978) 1327–1331.Google Scholar
  49. 49.
    Re, R. N., Bioburst: The Impact of Modern Biology on the Affairs of Man. Louisiana State Univ. Press, Baton Rouge 1986.Google Scholar
  50. 50.
    Roberts, R. M., Serendipity. Wiley, New York 1989.Google Scholar
  51. 51.
    Rothweiler, W., and Tamm, Ch., Isolation and structure of phomin. Experientia22 (1966) 750–752.Google Scholar
  52. 52.
    Rüegger, A., Kuhn, M., Lichti, H., Loosli, H. R., Huguenin, R., Quiquerez, C. and von Wartburg, A., Cyclosporin A, ein imunosuppressiv wirksamer, Peptidmetabolit ausTrichoderma polysporum (Link ex Pers.) Rifai. Helv. chim. Acta59 (1976) 1075–1092.PubMedGoogle Scholar
  53. 53.
    Rüsch, M. E., and Stähelin, H., Ueber einige biologische Wirkungen des Cytostaticum Verrucarin A. Arzneimittelforsch. (Drug Research)15 (1965) 893–897.Google Scholar
  54. 54.
    Sawada, S., Suzuki, G., Kawase, Y., and Takaku, F., Novel immunosuppressive agent, FK 506. In vitro effects on the cloned T cell activation. J. Immun.139 (1987) 1797–1803.PubMedGoogle Scholar
  55. 55.
    Sigg, H. P., Die Konstitution von Brefeldin A. Helv. chim. Acta47 (1964) 1401–1415.Google Scholar
  56. 56.
    Sigg, H. P., Mauli, R., Flury, E., and Hauser, D., Die Konstitution von Diacetoxyscirpenol. Helv. chim. Acta48 (1965) 962–988.Google Scholar
  57. 57.
    Sigg, H. P., and Weber, H. P., Isolierung und Strukturaufklärung von Ovalicin. Helv. chim. Acta.51 (1968) 1395–1408.PubMedGoogle Scholar
  58. 58.
    de Souza, N. J., Ganguli, B. N., and Reden, J., Strategies in the discovery of drugs from natural sources. Ann. Rep. med. Chem17 (1982) 301–310.Google Scholar
  59. 59.
    Stähelin, H., Ueber osmotisches Verhalten und Fusion nackter Protoplasten von Bac. anthracis. Schweiz. Zs. allg. Path. Bakt.17 (1954) 296–310.Google Scholar
  60. 60.
    Stähelin, H., Internal Report, Sandoz Pharma of July 13, 1959, on compound No. 9648 (phomin, cytochalasin B).Google Scholar
  61. 61.
    Stähelin, H., Internal Report Sandoz Pharma of October 6, 1960, on compound No. 11-247 (HPS 277, brefeldin A).Google Scholar
  62. 62.
    Stähelin, H., A simple quantitative test for cytostatic agents using non-adhering cells in vitro. Med. exp.7 (1962) 92–102.PubMedGoogle Scholar
  63. 63.
    Stähelin, H., Internal Report Sandoz Pharma of November 18, 1964, on compounds No. 7827 and 11-699/2.Google Scholar
  64. 64.
    Stähelin, H., 4′-Demethyl-epipodophyllotoxin thenylidene glucoside (VM 26), a podophyllum compound with a new mechanism of action. Europ. J. Cancer6 (1970) 303–311.Google Scholar
  65. 65.
    Stähelin, H., Ciclosporin: Historical background. Prog. Allergy38 (1986) 19–27.PubMedGoogle Scholar
  66. 66.
    Stähelin, H., Enhanced toxicity of the immunosuppressant ovalicin upon application to the skin. Experientia44 (1988) 611–613.PubMedGoogle Scholar
  67. 67.
    Stähelin, H., The development of immunosuppressive agents from x-rays to cyclosporin, in: Immunology 1930–1980, Essays on the History of Immunology, pp. 185–201. Ed. P. M. H. Mazumdar. Wall and Thompson, Toronto 1989.Google Scholar
  68. 68.
    Stähelin, H., and Cerletti, A., Experimentelle Ergebnisse mit den Podophyllum-Cytostatica SP-I und SP-G. Schweiz. med. Wschr.94 (1964) 1490–1502.Google Scholar
  69. 69.
    Stähelin, H., Kalberer-Rüsch, M. E., Signer, E., und Lazary, S., Ueber einige biologische Wirkungen des Cytostaticum Diacetoxyscirpenol. Arzneimittelforsch. (Drug Research)18 (1968) 989–994.Google Scholar
  70. 70.
    Stähelin, H., Karnovsky, M. L., Farnham, A. E., and Suter, E., Studies on the interaction between phagocytes and tubercle bacilli. III. Some metabolic effects in guinea pigs associated with infection with tubercle bacilli. J. exp. Med.105 (1957) 265–277.PubMedGoogle Scholar
  71. 71.
    Stähelin, H., and Trippmacher, A., Cytostatic activity of chlamydocin, a rapidly inactivated cyclic tetrapeptide. Europ. J. Cancer10 (1974) 801–808.Google Scholar
  72. 72.
    Stähelin, H., and von Wartburg, A. The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain Memorial Award Lecture. Cancer Res.51 (1991) 5–15.PubMedGoogle Scholar
  73. 73.
    Tamm, Ch., The antibiotic complex of the verrucarins and roridins. Fortschr. Chem. Org. Naturst.31 (1974) 63–117.Google Scholar
  74. 74.
    Tamura, G., Ando, K., Suzuki, S., Takatsuki, A., and Arima, K., Antiviral activity of brefeldin A and verrucarin A. J. Antibiotic.21 (1968) 160–161.Google Scholar
  75. 75.
    Thommen, K., Antimalarial activity of cyclosporin A. Agents and Actions11 (1981) 770–773.PubMedGoogle Scholar
  76. 76.
    Thompson, L., Jean-François Borel's transplanted dream. Washington Post, November 15, 1988.Google Scholar
  77. 77.
    Traxler, R., In der Pharma-Forschung beginnt die Zukunft in der Vergangenheit. Nordschweiz, September 23, 1988.Google Scholar
  78. 78.
    Weiner, E., Ueber die immunosuppressive Wirkung des Sesquiterpens Ovalicin auf Lymphozyten. Thesis, Univ. of Würzburg 1976.Google Scholar
  79. 79.
    White, D. J. G., and Calne, R. Y., The use of cyclosporin A immunosuppression in organ grafting. Immun. Rev.65 (1982) 115–131.PubMedGoogle Scholar
  80. 80.
    Wiederrecht, G., Lam E., Hung, S., Martin, M., and Sigal, N., The mechanism of action of FK-506 and cyclosporin A. Ann. N. Y. Acad. Sci.696 (1993) 9–19.PubMedGoogle Scholar
  81. 81.
    Wiskott, E., Sandimmun. Internat. Sandoz Gazette, March 1983.Google Scholar
  82. 82.
    Woodruff, M., Concluding Remarks, in: Cyclosporin A, pp. 569–573. Ed. D. J. G. White. Elsevier, Oxford 1982.Google Scholar
  83. 83.
    van Ypersele de Strihou, C., La cyclosporine. J. Pharm. Belg.40 (1985) 109–112.PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel 1996

Authors and Affiliations

  • H. F. Stähelin
    • 1
  1. 1.Basel(Switzerland)

Personalised recommendations