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Chemotherapy by Design

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A Master of Science History

Part of the book series: Archimedes ((ARIM,volume 30))

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Abstract

In 1988 the Nobel Prize in Physiology or Medicine was awarded jointly to Sir James W. Black, Gertrude B. Elion, and George H. Hitchings “for their discoveries of important principles for drug treatment.” The award to Elion and Hitchings recognized a collaboration that had yielded effective drugs for use in a remarkable variety of conditions, including cancer, gout, organ transplantation, malaria, and bacterial and viral infections. This article offers a description and analysis of the Hitchings-Elion research program: its grounding in the antimetabolite concept, and its implementation in the development of new drugs. Emphasis is on the coherence and unity of the program over more than four decades, its incorporation of both rational and empirical elements, and its character as industrialized research.

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Notes

  1. 1.

    Folke Sjöqvist, Presentation speech, in Nobel Lectures in Physiology or Medicine 1981–1990, Tore Frängsmyr, Editor-In Charge, and Jan Lindsten, Editor (Singapore: World Scientific Publishing Co., 1993), 409–411. Parts of this paper appeared in different form in John E. Lesch, The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine (New York: Oxford University Press, 2007), 256–268; and idem., “Dreams of reason: historical perspective on rational drug design,” 2008 Kremers Award Lecture, Pharmacy in History 50 (2008): 131–139.

  2. 2.

    George H. Hitchings, Autobiography, in Nobel Lectures in Physiology or Medicine 1981–1990, Tore Frängsmyr, Editor-in-Charge, and Jan Lindsten, Editor (Singapore: World Scientific Publishing Co., 1993), 471–475.

  3. 3.

    George H. Hitchings, “A biochemical approach to chemotherapy,” Drug Intelligence and Clinical Pharmacy 16 (November 1982): 843–848 (on 843).

  4. 4.

    D. D. Woods, “The relation of p-aminobenzoic acid to the mechanism of the action of sulphanilamide,” British Journal of Experimental Pathology 21 (1940): 74–90; D. D. Woods and P. Fildes, “The anti-sulphanilamide activity (in vitro) of p-aminobenzoic acid and related compounds” (abstract), Chemistry and Industry 18 (February 24, 1940): 133–134. On the background and formulation of the Woods-Fildes theory, see Lesch, The First Miracle Drugs (ref. 1), 251–262.

  5. 5.

    Paul Fildes, “A rational approach to research in chemotherapy,” Lancet 238 (1940): 955–957.

  6. 6.

    John S. Lockwood, “Progress toward an understanding of the mode of chemotherapeutic action of sulfonamide compounds,” in Chemotherapy, University of Pennsylvania Bicentennial Conference (Philadelphia: University of Pennsylvania Press, 1941), 9–28 (on 26).

  7. 7.

    Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 843 (quote); George H. Hitchings, Gertrude B. Elion, Elvira A. Falco, Peter B. Russell, and Henry VanderWerff, “Studies on analogs of purines and pyrimidines,” Annals of the New York Academy of Sciences 52, Art. 8 (July 7, 1950): 1318–1335; George H. Hitchings, “Selective inhibitors of dihydrofolate reductase,” Nobel Lecture, December 8, 1988, in Nobel Lectures in Physiology or Medicine 1981–1990, Tore Frängsmyr, Editor-in-Charge, and Jan Lindsten, Editor (Singapore: World Publishing Co., 1993), 476–493 (on 476).

  8. 8.

    Hitchings, “Selective inhibitors” (ref. 7), 476; Hitchings, Autobiography (ref. 2). On Elion, see below.

  9. 9.

    E. A. Falco, G. H. Hitchings, and M. B. Sherwood, “The effects of pyrimidines on the growth of Lactobacillus casei,” Science 102 (1945): 251–254; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 843; and Hitchings, “Selective inhibitors” (ref. 7), 476.

  10. 10.

    Hitchings, Autobiography (ref. 2).

  11. 11.

    Hitchings, “Selective inhibitors” (ref. 7), 476–477; and Hitchings, Autobiography (ref. 2).

  12. 12.

    Hitchings, Autobiography (ref. 2).

  13. 13.

    Hitchings, “Selective inhibitors” (ref. 7), 477; Joseph H. Burchenal, David A. Karnovsky, Elizabeth M. Kingsley-Pillers, Chester M. Southam, W. P Laird Meyers, George C. Escher, Lloyd F. Craver, Harold W. Dargeon, and Cornelius P. Rhoads, “The effects of the folic acid antagonists and 2, 6-diaminopurine on neoplastic disease, with special reference to acute leukemia,” Cancer 4 (1951): 549–569.

  14. 14.

    Autobiography of Gertrude B. Elion, “The Nobel Prize in Physiology or Medicine 1988,” The Oncologist 11 (2006): 966–968.

  15. 15.

    Elion, “Autobiography” (ref. 14), 967.

  16. 16.

    Sidney Farber, Louis K. Diamond, Robert D. Mercer, Robert F. Sylvester, and James A. Wolff, “Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin),” New England Journal of Medicine 238 (1948): 787–793.

  17. 17.

    Farber, “Temporary remissions in acute leukemia in children” (ref. 16), 787, 793.

  18. 18.

    Walter Sneader, Drug Discovery: A History (Chichester, UK: Wiley, 2005), 248–249. On the Lederle Laboratories work on folic acid, see Y. SubbaRow et al., “Folic acid,” Annals of the New York Academy of Sciences 48 (1946): 255–349; and M.E. Hultquist, et al., “Folic acid (supplement). Synthesis of pteroylglutamic acid (Liver L. casei factor) and pteroic acid—Part II,” Annals of the New York Academy of Sciences 48, Art. 5 (supplement) (1947): i–vi.

  19. 19.

    Sneader, Drug Discovery (ref. 18), 249.

  20. 20.

    Sneader, Drug Discovery (ref. 18), 249–250; Sidney Farber, Elliott C. Cutler, James W. Hawkins, J. Hartwell Harrson, E. Converse Peirce, 2nd, and Gilbert G. Lenz, “The action of pteroylglutamic conjugates on man,” Science 106 (1947): 619–621; Farber et al., “Temporary remissions in acute leukemia in children” (ref. 16), 787. On nitrogen mustard as a cancer chemotherapy, see Alfred Gilman and Frank S. Philips, “The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides,” Science 103 (1946): 409–436; and Rose J. Papac, “Origins of cancer therapy,” Yale Journal of Biology and Medicine 74 (2001): 391–398.

  21. 21.

    James M. Smith, Jr., Donna B. Cosulich, Martin E. Hultquist, and Doris R. Seeger, “The chemistry of certain pteroylglutamic acid antagonists,” Transactions of the New York Academy of Sciences, Series II, 10 (1948): 82–83; Anthony S. Travis, “From color science to polymers and sulfa drugs: Calco Chemical Company and American Cyanamid between two World Wars,” Chemical Heritage 23, 3 (Fall 2005): 8–13.

  22. 22.

    Richard O. Roblin, Jr., “Metabolite antagonists,” Chemical Reviews 38 (1946): 255–377 (on 255 and 366).

  23. 23.

    A. L. Franklin, E. L. R. Stockstad, M. Belt, and T. H. Jukes, “Biochemical experiments with a synthetic preparation having an action antagonistic to that of pteroylglutamic acid,” Journal of Biological Chemistry 169 (1947): 427–435; B. L. Hutchings, J. H. Mowat, J. J. Oleson, E. L. R. Stockstad, J. H. Boothe, C. W. Waller, R. B. Angier, J. Semb, and Y. SubbaRow, “Pteroylaspartic acid, an antagonist for pteroylglutamic acid,” Journal of Biological Chemistry 170 (1947): 323–328; Sneader, Drug Discovery (ref. 18), 250–251. For an early clinical report on amethopterin, see Leo M. Meyer, Franklin R. Miller, Manuel J. Rowen, George Bock, and Julius Rutzky, “Treatment of acute leukemia with amethopterin (4-amino, 10-methyl pteroylglutamic acid),” Acta Haematologica 4, 3 (1950): 157–167.

  24. 24.

    Hitchings, Autobiography (ref. 2).

  25. 25.

    Hitchings, “Selective inhibitors” (ref. 7), 476.

  26. 26.

    Gertrude B. Elion, “The purine path to chemotherapy,” Nobel Lecture, December 8, 1988, Nobel Lectures in Physiology or Medicine 1981–1990, Tore Frängsmyr, Editor-in-Charge, and Jan Lindsten, Editor (Singapore: World Publishing Co., 1993), 447–468 (on 449); Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 843–844.

  27. 27.

    Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 844; Roy Waldo Miner, editor, 6-Mercaptopurine, Annals of the New York Academy of Sciences 60 (December 6, 1954): 183–508.

  28. 28.

    Elion, “The purine path to chemotherapy” (ref. 26), 449; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 844.

  29. 29.

    Elion, “The purine path to chemotherapy” (ref. 26), 449; Cornelius P. Rhoads, editor, Antimetabolites and Cancer. A symposium presented on December 28–29, 1953 at the Boston meeting of the American Association for the Advancement of Science (Washington, DC: American Association for the Advancement of Science, 1955); Sneader, Drug Discovery (ref. 18), 253. On childhood leukemia see also John Laszlo, The Cure of Childhood Leukemia: Into the Age of Miracles (New Brunswick: Rutgers University Press, 1996). On the status of antimetabolite research by the early 1950s, see D. W. Woolley, A Study of Antimetabolites (New York: Wiley, 1952).

  30. 30.

    Elion, “The purine path to chemotherapy” (ref. 26), 449–451; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 844.

  31. 31.

    Elion, “The purine path to chemotherapy” (ref. 26), 451–452; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 844; Sneader, Drug Discovery (ref. 18), 253.

  32. 32.

    Elion, “The purine path to chemotherapy” (ref. 26), 452; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 844–845; Sneader, Drug Discovery (ref. 18), 253.

  33. 33.

    Elion, “The purine path to chemotherapy” (ref. 26), 452; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 845.

  34. 34.

    Elion, “The purine path to chemotherapy” (ref. 26), 452; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 845.

  35. 35.

    Elion, “The purine path to chemotherapy” (ref. 26), 452; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 845.

  36. 36.

    Elion, “The purine path to chemotherapy” (ref. 26), 452–453; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 845; George H. Hitchings and Gertrude B. Elion, “Chemical suppression of the immune response,” Pharmacological Reviews 15 (1963): 365–405; G. Wolberg, “Antipurines and purine metabolism,” in M. A. Bray and J. Morley, editors, The Pharmacology of Lymphocytes, Handbook of Experimental Pharmacology 85 (1988): 517–533.

  37. 37.

    Elion, “The purine path to chemotherapy” (ref. 26), 453; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 845–846; Sneader, Drug Discovery (ref. 18), 254.

  38. 38.

    Elion, “The purine path to chemotherapy” (ref. 26), 453–456; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 845–846; Sneader, Drug Discovery (ref. 18), 254.

  39. 39.

    Falco, Hitchings, and Sherwood, “The effects of pyrimidines on the growth of Lactobacillus casei” (ref. 9); Hitchings, Autobiography (ref. 2); Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 846.

  40. 40.

    Hitchings, “Selective inhibitors” (ref. 7), 476–477; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 846.

  41. 41.

    Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 846; Hitchings, “Selective inhibitors” (ref. 7), 477–478.

  42. 42.

    George H. Hitchings, “The utilisation of biochemical differences between host and parasite as a basis for chemotherapy,” in L. G. Goodwin and R. H. Nimmo-smith, editors, Drugs, Parasites, and Hosts (Boston: Little, Brown and Company, 1962), 196–210; George H. Hitchings and Sheila L. Smith, “Dihydrofolate reductases as targets for inhibitors,” Advances in Enzyme Regulation 18 (1980): 349–371; Hitchings, “Selective inhibitors” (ref. 7), 477–481; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 486–487.

  43. 43.

    Hitchings, “Selective inhibitors” (ref. 7), 482; Hitchings, “A biochemical approach to chemotherapy” (ref. 3), 847. On trimethoprim, including doubts about the utility of the trimethoprim-sulfamethoxazole combination, and the eventual marketing of trimethoprim as a stand-alone drug, see also David Greenwood, Antimicrobial Drugs: Chronicle of a Twentieth Century Medical Triumph (Oxford and New York: Oxford University Press, 2008), 254–256.

  44. 44.

    Hitchings, Autobiography (ref. 2); Elion, “Autobiography” (ref. 14), 967.

  45. 45.

    Elion, “The purine path to chemotherapy” (ref. 26), 456–457; Sneader, Drug Discovery (ref. 18), 259; F. M. Schabel, Jr., “The antiviral activity of 9-b-D-arabinofuranosyladenine (ara-A),” Chemotherapy 13 (1968): 321–338.

  46. 46.

    Elion, “The purine path to chemotherapy” (ref. 26), 457–458.

  47. 47.

    Elion, “The purine path to chemotherapy” (ref. 26), 458.

  48. 48.

    Elion, “The purine path to chemotherapy” (ref. 26), 458; Sneader, Drug Discovery (ref. 18), 259; Gertrude B. Elion, Phillip A. Furman, James A. Fyfe, Paulo de Miranda, Lilia Beauchamp, and Howard J. Schaeffer, “Selectivity of action of an antiherpetic agent, 9-(hydroxyethoxymethyl) guanine,” Proceedings of the National Academy of Sciences 74 (December 1977): 5716–5720; H. J. Schaeffer, Lilia Beauchamp, P. de Miranda and Gertrude B. Elion, “9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group,” Nature 272 (April 1978): 583–585. On acyclovir see also Greenwood, Antimicrobial Drugs (ref. 43), 375–378.

  49. 49.

    Gertrude B. Elion, “The chemotherapeutic exploitation of virus-specified enzymes,” Advances in Enzyme Regulation 18 (1980): 53–66; Elion, “The purine path to chemotherapy” (ref. 26), 458–463; Sneader, Drug Discovery (ref. 18), 259.

  50. 50.

    Elion. “The purine path to chemotherapy” (ref. 26), 462–463; Sneader, Drug Discovery (ref. 18), 259.

  51. 51.

    Sneader, Drug Discovery (ref. 18), 260–261.

  52. 52.

    Sneader, Drug Discovery (ref. 18), 260–261.

  53. 53.

    Sneader, Drug Discovery (ref. 18), 261.

  54. 54.

    George H. Hitchings, “The Bertner Foundation Memorial Award Lecture—salmon, butterflies, and cancer chemotherapy,” Pharmacological Basis of Cancer Chemotherapy (Baltimore: The Williams & Wilkins Company, 1975), 25–43 (on 30).

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  1. University of California, Berkeley, CA, USA

    John E. Lesch

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Correspondence to John E. Lesch .

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  1. , Div. Humanities & Social Sciences, California Institute of Technology, E. California Blvd. 1200, Pasadena, 91125, California, USA

    Jed Z. Buchwald

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Lesch, J.E. (2011). Chemotherapy by Design. In: Buchwald, J. (eds) A Master of Science History. Archimedes, vol 30. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2627-7_16

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