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ANTI-METABOLITES FOLIC ACID and derivitives In 1944, Leuchtenberger found that folic acid strongly inhibited tumour growth in mice(1); and a year later Lewisohn et al reported that with folic acid "Complete regression of spontaneous breast in mice were observed in 39 among 89 animals"(2). However, in 1947, when Farber used folic acid derivatives clinically, he reported folic acid accelerated the progress of leukaemia in humans and led to death(3). So a search began for folic acid antagonists.
FOLIC ACID ANTAGONISTS AN-FOL and MET-FOL Between 28 Mar and 4 Apr 1947, Farber gave the first folic acid antagonists, an-fol, to 8 children with acute leukaemia; and another, met-fol, to 7 children with acute leukaemia(4). Farber reported (later) the compounds had produced effects on the leukaemic process in bone marrow of children but were weak antagonists(5). Farber et al first described their clinical use of the two antagonists in their paper published by the ` In 1947, Hutchings et al intramuscularly injected day-old * Farber had first used an early antagonist, clinically from 28 March to 4 April 1947(8) before Hutching`s paper on animal experiments was even received - on 7 June 1947 - for publication(9). AMINOPTERIN, AMINO-AN-FOL, AMETHOPTERIN (METHOTREXATE) Between 3 Dec 1947 and 15 April 1948, Farber gave aminopterin to 16 children with acute leukaemia(10), and reported "The first impressive remissions in the course of acute leukaemia were produced... These were characterized by a return almost to normal state in some, and to a state almost indistinguishable from normal in others, in a group of 10 of 16 children with acute leukaemia". On 25 Aug 1948, Farber informed the Congress of the international Society of Haemotology, in Buffalo, New York, that 60 children with acute leukaemia had been treated with aminopterin, amethopterin (methotrexate) or amino-an-fol and that more than half of the patients had shown clinical improvement. Farber also referred to observations by Dr Louis Diamond of the Boston Children`s Hospital of complete or partial remissions in 30 of 300 children with acute leukaemia; and findings by Dr George Guest of Cincinatti Children`s Hospital of five consecutive remissions. Farber thought that someone might observe deaths within two weeks of treatment, so - for comparison - he took a limit of three weeks after treatment and noted "During this period, those patients most severely involved will have died or the folic acid antagonists employed will have had an opportunity to effect tumour infiltrations in the viscera and the bone marrow"(11). There is no record of these folic acid antagonists - aminopterin, amethopterin (methotrexate), or amino-an-fol - having been previously tested on mouse tumours prior to Farber`s clinical administration of the drugs in children(12). On 10 Nov 1948, `Cancer` received a paper by Suguira et al describing inhibiting effects of aminopterin on growth in mice of sarcoma 180, mammary adenocarcinoma EO771, and Harding-Passey melanoma - but the drug had no destructive action on the tumours(22). In 1949, Law et al reported that the therapeutic dose varied between different strains of mice(13), and in the same year, F S Philips and J B Thiersch noted rats and mice suffered weight loss, weakness, under-development of bone marrow tissue, and intestinal ulceration(14); and, in another report, that similar effects were seen in dogs, in which there was also an abnormal form of the precursors of red blood cells in the bone marrow of the dogs(15). On 11 Mar 1951, Dr Ezra Greenspan of the Clinical Research Unit, NCI, commented "Some time ago, we noted that there were sex differences in the toxicity of aminopterin in a number of strains of adult mice. The tolerated dose in males was approximately one-half that in females"(16). On 9 Nov 1948, `Cancer` received a paper by Burchenhal et al who wrote in the opening paragraph "promising results of Farber et al in the clinical mangement of acute leukaemia in children by folic acid derivitives, 4-amino-pteroyglutamic acid (aminopterin) and 4-amino-N10-methyl-pteroylglutamic acid (amethopterin) suggested the advisability of testing these drugs on transmitted mouse Leukaemia" - admitting that the drugs had first been used clinically. Burchenal et al tested the drugs in mice - injected with chloroleukaemia Ak1394, or lymphoid leukaemia Ak9417; and against lymphoid leukaemia Ak4, or myleoid leukaemia C1498 in C57 black mice; and recorded varying results. Aminopterin had only slight, irregular activity in prolonged "survival" time of mice with Ak1394 and Akm9417; and was slightly to moderately effective against Ak4 and C1498. Amethopterin was ineffective against Ak1394, but "survival" in mice with Akm9417, Ak4, and C1498 was as great as, or greater than, in mice treated with nitrogen mustards(17). Although Burchenhal`s paper was published before Farber`s, Farber had presented clinical evidence to the International Society of Haematology Congress on 25 August 1948 - 10 weeks before Burchenhal`s paper was received for publication. Farber`s paper appeared less than a month after Burchenhal`s. On 17 Apr 1949, a paper was received for publication from J B Thiersch, who wrote that aminopterin and amethopterin had caused depletion of red cell elements in marrow of CFW mice bearing sarcoma 180 tumours, depletion of red cell production in blood-forming tissue of marrow in rats, degrees of under-development of marrow in guinea pigs, marked reduction of marrow elements in pigs(18). A subsequent paper by Burchenhal et al was recived for publication on 18 Mar 1949, referring to tests against transmitted leukaemia Ak4 in mice - with 82 of 90 compounds related to folic acid showing no chemotherapeutic effect. In mice treated with aminopterin, amethopterin, or diaminopurine,the average "survival time" doubled(19) but "survival" in days of treated mice varied between four different folic acid antagonists tested, and within mice in the same group, given the same dose of the same drug(20). On 11 Mar 1951, at the Second Conference on Folic Acid Antagonists, James Williams stated that the drugs showed: "a rather wide spectrum of activity against tumours of various types [in animals]... it is difficult to draw profound conclusions from our data in view of the differences in dosage levels used"(21). Farber told the audience: "we have tried a great many of them (folic acid antagonists), some of which Dr Williams showed you on the slides. May I bring what might become a long discussion to an abrupt end by saying that no results have been achieved in children with acute leukaemia with use of any of these compounds that are better than those obtained with aminopterin and amethopterin"(22). In 1972, A Geribtzoff et al reported that methotrexate does not have the same toxicity in rabbits and guinea pigs as most other species(23). The `British Nation Formulary` record the types of cancer for which methotrexate has been deployed - including cancers of the head and neck, and of the breast(24). In 1988, two members of the Institute for Cancer Research at the Royal Marsden Hospital assessed the response rate of various types of cancer to drug therapy. For cancers of the head and neck, they recorded a response rate of 50%; and for cancer of the breast, a rate of less than 50%; in those treated with methotrexate(25). PURINE ANTAGONISTS AZAGUANINE Roblin et al prepared a compound, azaguanine, in 1944(26), which was then tested as an anti-bacterial agent(27). Kidder reported, in 1949, that azaguanine was an antagonist of guanine in the metabolism of tetrahymena geleii. Tested it on mice, it inhibited growth of transplanted mammary adenosarcoma(28). In 1949, Kidder(29), and Armistead(30), gave azaguanine to seven patients, who all developed toxic dermatitis and showed no signs of any clinical improvement(31). In 1950, Straus gave the drug to five patients with Hodgkin`s disease, without any clinical benefit(32). In 1952, B P Wright and others noted no improvement in eight patients, who experienced vomiting, diarrhoea, pruritis, and reduction in the number of white blood cells resulted, due to toxicity(33); and Colsky et al administered it to 12 patients with advanced cancer but it had no anti-cancer effect, and caused marked toxicity(34). In 1953, Gellhorn gave the drug to eleven patients, who experienced vomiting, skin eruptions, and obstruction of a vein by blood clot(35), and with 24 hours the drug had metabolised and was excreted as 8-azaguanine(36) which had no anti-tumour effect(37). By 1956, Farber noted: "Active clinical investigation of 8-azaguanine appears to have ceased"(37). In 1965, L Larinonov noted, in `Cancer Chemotherapy`, that this purine had been shown to inhibit certain animal tumours, but was a complete failure for treatment of human cancer(38). DIAMINOPURINE After examination of inhibitors of growth of L casei bacteria, purine anti-metabolites were synthesized in 1948 by George Hitchings et al at Wellcome Research Laboratories, Tuckahoe, New York(39). Gertrude Belle Elion sent compounds off to be tested for their ability to stem mouse tumour growth(40). A relatively acute lymphoid strain of leukaemia, Ak4, was transplanted into 298 mice - 97 received intraveneous injections of the new compound, diaminopurine; 42 nitrogen mustard; 61 amethopterin; 98 were untreated "controls" - and, comparing the results of the effects of three drugs used in mice, they reported that "2,6-diaminopurine, in maximum doses, has proved considerably more effective than the standard nitrogen mustard... and approximately as effective as 4-amino-N10-methyl-PGA (aminopterin)"(41). A clinical trial was arranged at the Memorial Hospital(42). On the basis of US NCI rules, the initial human dose should have been one-third of the maximum tolerated dose in the most sensitive species(45), which in mice had been 42mg of the drug per kg body weight of the patient - but, clinically, it was found that excess of 10mg/kg induced vomiting, diarrhoea, and depression of bone marrow(46). Although doses of 10mg/kg or less were considered to have been "well tolerated"(47), diaminopurine was less effective than aminopterin(48) - but tests in mice had shown that diaminopurine was as effective as aminopterin(49). In human patients, diaminopurine caused gastro-intestinal side-effects, which, as Farber wrote in 1956, "seriously limited its usefulness and is now only of historical interest"(50). Ultimately, drug toxicity proved to be too high, so in the 1950s, diaminopurine was rejected as a leukaemia treatment(51). MERCAPTOPURINE In 1952, Elion, Hitchings and Elizabeth Burgi introduced 6-mercaptopurine, a more potent antimetabolite that had originally been made purely as a chemical intermediate for the synthesis of more 6-aminopurines. Screening revealed that mercaptopurine inhibited growth of L casei, so it was sent to the Slaon-Kettering Institute for testing(52). As an anti-cancer agent, it was at first negative, then of low activity in S180 sarcoma in mice(53); inhibited growth of some tumours in rats and mice(54); produced under-development of bone marrow and gastro-intestinal changes in mice and dogs, and focal necrosis of the liver in dogs(55). In 1953, Lloyd Law noted activity in L1210 leukaemia in mice(56). Mercaptopurine was used clinically at Memorial Hospital, in 1953, by Burchenhal, who found it to be of little or no value in lymphomas, chronic lymphocytic leukaemia, neuroblastoma, numerous sarcomas and carcinomas, but was effective against acute leukaemia(56) - leading to him to reason, a year later, it was the drug of choice in acute leukaemia in adults(57), and later stated: "It would be unwise... to rule out irrevocably a compound on the basis of a negative effect against experimental tumours [in animals]"(58). THIOGUANINE Thioguanine, an analogue of mercaptopurine(59), was tested by Philips et al against a 6-mercaptopurine-resistant strain of sarcoma 180 in mice. In 1954, experimenters reported that thioguanine was ineffective. In rats and dogs, it was a bone marrow depressant; but in dogs was not toxic to the liver nor did it cause the gastrointestinal effects seen with 6-mercaptopurine(60). In 1954, thioguanine was used clinically. Burchenhal et al gave the drug to three patients with chronic myelocytic leukaemia, all of whom responded to treatment(61). Sidney Farber treated 48 children with acute leukaemia at the Children`s Cancer Research Foundation. The longest remission lasted 16 months - with mean rate of about 6 months. Farber referred to clinical side effects, which tests in dogs had not revealed: "Although thioguanine produced no liver damage in dogs, such an effect may be produced in [hu]man[s]. A child given 2 mg/kg daily developed hepatomegaly [enlargement of the liver], ascites [accumulation of fluid in the peritoneal cavity], jaundice.."(62).
ANTI-PYRAMIDES AMINOGLUTHIMIDE In 1958, a US patent was issued for aminogluthimide(63), which was brought onto the market in 1960 after Ciba researchers found that it was a strong anti-convulsant (but had weaker sedative and hypnotic properties). When the drug was used for a period of five months in 1963 to control epilepsy in a young girl, Ralph Cash, a paediatrician at the Sinai Hospital in Detroit, USA, noticed that the drug had induced typical signs of Addison`s disease. Following Cash`s finding, other doctors, elsewhere, made similar reports. An investigation revealed that aminoglutethimide blocked steroid biosynthesis. Cash demonstrated that the drug formed pregneolone - a prerequisite for steroid hormone synthesis. Subsequently, it was given to patients with Cushing`s disease in the hope that they might benefit from the drug`s ability to inhibit over-production of corticosteroids, but the results were disappointing(64). Thomas Griffiths et al of Harvard Medical School administered aminoglutethimide to a woman with metastatic breast cancer. When used in 9 patients, only 3 had remissions. Studies at Pennsylvania State University, Duke University, and University of Oregon, led to more successful results(65). In 1981, Asbury reported on clinical studies of its use in metastatic breast cancer(66). A year later, it was included in the `British National Formulary` as a treatment of metastatic mammary carcinoma in post-menopausal women(67). Murray and Pitt published, in 1985, the results of a clinical study of aminoglutemide`s use in cases of advanced prostatic carcinoma(68). CYTARABINE A new type of thymine derivative was isolated by Prof Werner Bergman and Robert Feeney in 1951, from a sponge collected from the waters off Florida. In 1956, Bergman and David Burke isolated a similar uracil derivative and described the structure of both of the compounds as "spongo-nucleosides"(69). Biologic activities of ribonucleotides found in sponges led to interest in the synthesis, by various chemists, of various related compounds(70). One of the compounds, cytarabine, was synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker in the biochemistry department of the University of California, Berkeley(71). In 1964, John Evans et al of the Upjohn Company tested activity of the compounds against transplanted sarcoma 180 tumours in mice(72). Cytarabine was used clinically and in 1968 Rose Ruth Ellison, for the leukaemia Group B - formed from collaboration between Roswell Park and US National Cancer Institute in 1964(73) reported on the drug`s activity in acute myelogenous leukaemia (74). It was the only one of the synthesized compounds to have useful clinical activity, with its main clinical use being in the treatment of acute leukaemia(75). But in 1971, Dr Thomas Hall of University of Hawaii Cancer Center, Honolulu, commented in `NCI Monograph`, "the concept that cytosine arabinoside [cytarabine] would be best given by prolonged intravenous infusion in man, arose because of the findings that this type of therapy was best for tumour-bearing mice. However, on clinical trial no benefit can be shown for prolonged infusion in leukaemic [hu]man[s]... Most human tumours including leukaemias are vastly different biologically from transplanted mouse leukaemias"(76). refs 1. Farber,S et al. Science. vol 106. 1947. 2. Sneader,W. drug Discovery. John Wiley & Sons. 1985. 3. Farber,S et al. NEJM. vol 238. 1948. 4. ibid. 5. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 6. Farber,S et al. NEJM. vol 238. 1948. 7. Hutchings,J H et al. J Biol Chem. vol 170. 1947. 8. Farber,S et al. NEJM. vol 238. 1948. 9. Hutchings,J H et al. J Biol Chem. vol 170. 1947. 10. Farber,S et al. NEJM. vol 238. 1948. 11. Farber,S. Blood. vol 4. 1949. 12. Shimkin,MB. Some Classics in Experimental Oncology. NIH Pub. 1980. 13. Law,L W et al. J of NCI. vol 10. 1949-50. 14. Phillips,F S. Thiersch,J B. J Pharm Exp Ther. vol 95. 1949. 15. Thiersch,J. Phillips,F. Proc Soc Exp Bio. Med. vol 71. 1949. 16. Greenspan,E M. IN: Blood. vol 7. 1952. 17. Burchenhal,J H et al. Cancer. 2. 1949. 18. Thiersch,JB. Cancer. 2. 1949. 19. Svodoba,G H. LLoydiin. vol 24. 1961. 20. Sneader,W. 1989. op cit. p357. 21. Burchenhal,J H et al. Proc Soc Bio Med. vol 71. 1949. 22. Farber,S. Blood. 7. 1952 23. Gerebtzoff,A et al. IN: Elliott,H et al [eds]. Annual Reviews of Pharmacology. vol 12. 1972 24. British National Formulary. 1982. no 4. 25. Calvert,H. McElwain,T. IN: Tiffany,R. Pritchard,P [eds]. 1988. Oncology for Nurses & Health Care Prof. Harper & Row/Beaconsfield. table 13.2 p299 26. Roblin,R O Jnr et al. J Am Chem Soc. vol 671. 1945. 27. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 28. Kidder,G W. Dewey,V C. J Biol Chem. vol 179. 1949. 29. Kidder,G W et al. Science. vol 109. 1949. 30. Armistead,G C Jnr et al. 1949. Cancer. vol 2. 1949. 31. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 32. Straus,B et al. Blood. vol 2. 1950. 33. Wright,B P et al. Harlem Hos Bull. vol 4. 1952. 34. Colsky,J et al. Cancer. vol 5. 1952. 35. Gellhorn,A. Cancer. vol 6. 1953. 36. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 37. ibid. 38. Larionov,L. Cancer Chemotherapy. Pergamon Press. 1965. 39. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 40. Scientific American. October 1991. 41. Burchenhal,J H et al. Cancer. vol 2. 1949. 42. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 43. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 44. Israel,L. Conquering Cancer (translation by Pinkman,J). Allen Lane. 1979. 45. Owens,A H. J Chron Dis. vol 15. 1963. 46. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 47. ibid. 48. Burchenhal,J H et al. 1949a. op cit. p120. 49. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 50. Scientific American. October 1991. 51. Sneader,W. Drug Discovery. John Wiley & Sons. 1989. 52. Clarke,D A et al. Cancer Research. vol 13. 1953. 53. ibid. 54. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 55. Law,L. Proc Soc Exp Biol Med. vol 84. 1953. 56. Burchenhal,J H. Merck report. vol 62. 1953. 57. Burchenhal,J H. Bull N Y Acad Med. vol 30. 1954. 58. Burchenhal,JH. quoted in Reines,B. Cancer Research on Animals. NAVS (Chicago). 1986.
59. Pratt,W B. Ruddon,R W. The Anticancer Drugs. Oxford University Press. 1979. 60. Philips et al. 1954. cited IN: Farber,S et al. Advances in Cancer Research vol IV. 1956. 61. Burchenhal,J H et al. 1954. cited IN: Farber,S et al. Advances in Cancer Research. vol IV. 1956. 63. Farber,S et al. Advances in Cancer Research. vol IV. 1956. 64. Merck Index. 11th ed. Merck. 1989. 65. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 66. Asbury. Cancer. vol 47. 1981. 67. British National Formulary. 1982. 68. Murray,R. European Journal of Cancer. vol 21. 1985. 69. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 70. Zubrud,CG. Semianrs in Oncology. vol 6. 1979. 71. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 72. Evans,J et al. Cancer Research. vol 24. 1964. 73. Zubrod,C G. Seminars in Oncology. vol 6. 1979. 74. Ellison,R R et al. Blood. vol 32. 1968. 75. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 76. Hall,T C. 1971. NCI (National Cancer Institute) Monograph.
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