Skip to main content

Arsenic-Based Drugs: From Fowler’s Solution to Modern Anticancer Chemotherapy

Part of the Topics in Organometallic Chemistry book series (TOPORGAN,volume 32)

Abstract

Although arsenic is a poison and has a predominantly unfavorable reputation, it has been used as pharmaceutical agent since the first century bc. In 1786, Thomas Fowler reported the effects of arsenic in the cure of agues, remittent fevers, and periodic headaches. From this time on and despite abusive use, some interesting indications began to appear for trypanosomiasis, syphilis, and blood diseases. The first significant organoarsenical drug (atoxyl) was synthesized by Pierre Antoine Béchamp in 1859 by chemically reacting arsenic acid with aniline but additional experimentations on the properties of arsenic led Paul Ehrlich, the founder of chemotherapy, to the discovery of salvarsan in 1910. From the Second World War, Ernst A.H. Friedheim greatly improved the treatment of trypanosomiasis by melaminophenyl arsenicals. Until the 1990s some organoarsenicals were used for intestinal parasite infections but carcinogenic effects were displayed and all the drugs have been withdrawn in USA, in Europe, and elsewhere. In 2003, arsenic trioxide (Trisenox®) was re-introduced for the treatment of very specific hematological malignancies.

Keywords

  • Atoxyl
  • Leukemia
  • Melarsoprol
  • Salvarsan
  • Syphilis
  • Trypanosomiasis
  • Tryparsamide

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-642-13185-1_1
  • Chapter length: 20 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   309.00
Price excludes VAT (USA)
  • ISBN: 978-3-642-13185-1
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   399.99
Price excludes VAT (USA)
Hardcover Book
USD   499.99
Price excludes VAT (USA)
Fig.1
Fig.2
Fig.3
Fig.4
Fig.5
Fig.6
Fig.7
Fig.8
Fig.9
Fig.10

Abbreviations

APL:

Acute promyelocytic leukemia

CML:

Chronic myeloid leukemia

CNS:

Central nervous system

HAT:

Human African trypanosomiasis

HIV:

Human Immunodeficiency Virus

Mel:

Melarsen

Mel B:

Melarsoprol

Mel W:

Melarsonyl potassium

References

  1. Ralph SJ (2008) Arsenic-based antineoplastic drugs and their mechanisms of action. Met Based Drugs 2008:260146

    CrossRef  Google Scholar 

  2. Li S, Luo X (2003) Compendium of materia medica. Foreign Languages Press, Beijing

    Google Scholar 

  3. Jackson R, Grainge JW (1975) Arsenic and cancer. Can Med Assoc J 113:396–401

    CAS  Google Scholar 

  4. Evens AM, Tallman MS, Gartenhaus RB (2004) The potential of arsenic trioxide in the treatment of malignant disease: past, present, and future. Leuk Res 28:891–900

    CrossRef  CAS  Google Scholar 

  5. Lipscomb JD (1877) Improvement in remedy for fevers. US Patent 186,141

    Google Scholar 

  6. Ramsaur MH (1869) Improved medical compound. US Patent 92,209

    Google Scholar 

  7. Lentilius R (1684) Ephémérides des curieux de la nature. Dec. 11, an 3 - Obs. 46

    Google Scholar 

  8. Friceius M (1710) Cap 2. Tractus de Virtute Venenorum Medica

    Google Scholar 

  9. Frank J (1835) Encyclopédie des Sciences Médicales ou traité général méthodique et complet des diverses branches de l'art de guérir. Deuxième division, Médecine : pathologie médicale. Bureau de l'Encyclopédie, Paris

    Google Scholar 

  10. Fowler T (1786) Medical reports on the effects of arsenic in the cure of agues, remittent fevers and perodic headaches

    Google Scholar 

  11. Hunt T (1848) Minimum fatal dose of arsenic. Prov Med Surg J 12:445

    Google Scholar 

  12. Hunt T (1848) On Dr. Castle's case of supposed poisoning by Fowler's solution. Prov Med Surg J 12:391

    Google Scholar 

  13. Bouteille B, Oukem O, Bisser S et al (2003) Treatment perspectives for human African trypanosomiasis. Fundam Clin Pharmacol 17:171–181

    CrossRef  CAS  Google Scholar 

  14. Steverding D (2008) The history of African trypanosomiasis. Parasit Vectors 1:3

    CrossRef  Google Scholar 

  15. Livingstone D (1858) Arsenic as a remedy for the tse tse bite. Br Med J 1:360–361

    CrossRef  Google Scholar 

  16. Manchester K (2001) Antoine Béchamp: père de la biologie. Oui ou non? Endeavour 25:68–73

    CrossRef  CAS  Google Scholar 

  17. Béchamp A (1863) De l'action de la chaleur sur l'arséniate d'aniline et de la formation d'un anilide de l'acide arsénique. Compt Rend 56:1172–1175

    Google Scholar 

  18. Thomas H (1905) Some experiments in the treatment of trypanosmiasis. Br Med J 1:1140–1143

    CrossRef  CAS  Google Scholar 

  19. Scherber G (1907) The atoxyl treatment of syphilis. Wien Klin Wochenschr 20:1165–1172

    CAS  Google Scholar 

  20. Blumenthal F (1902) Über Metaarsensäureanilid (atoxyl). Med Woche 3:163

    Google Scholar 

  21. Ehrlich P, Bertheim A (1907) Über p-Aminophenylarsinsäure. Ber Dtsch Chem Ges 40:3292–3297

    CrossRef  CAS  Google Scholar 

  22. Anonymous (1910) Action of Atoxyl on Eyes. Cal State J Med 8:384

    Google Scholar 

  23. Knopf H, Fabian R (1909) Further results of Atoxyl treatment. Berl Klin Wochenschr 46:99–101

    CAS  Google Scholar 

  24. Jacobs WA, Heidelberger M (1919) Aromatic arsenic compounds. II. The amides and alkylamides of N-arylglycine arsonic acids. J Am Chem Soc 41:1809–1821

    CrossRef  CAS  Google Scholar 

  25. Pearce L (1925) Tryparsamide treatment of African sleeping sickness. Science 61:90–92

    CrossRef  CAS  Google Scholar 

  26. Pearce L (1921) Treatment of human trypanosomiasis with tryparsamide (sodium salt of N-phenylglycineamide-p-arsonic acid). J Exp Med 34(1):1–104

    CrossRef  CAS  Google Scholar 

  27. Hawking F (1941) Drug resistance acquired during the treatment of sleeping sickness with tryparsamide and with Bayer 205. Am J Trop Med 21:469–475

    CAS  Google Scholar 

  28. Friedheim EAH (1944) Trypanocidal and spirochetocidal arsenicals derived from s-triazine. J Am Chem Soc 66:1775–1778

    CrossRef  CAS  Google Scholar 

  29. Friedheim EAH (1942) Substituted [1,3,5-triazinyl-(6)]-aminophenyl-arsonic acids and process for manufacture of same. US Patent 2,295,574

    Google Scholar 

  30. Doak G, Steinman H, Eagle H (1944) Arsenoso compounds containing amide groups. J Am Chem Soc 66:194–197

    CrossRef  CAS  Google Scholar 

  31. Banks C, Gruhzit O, Tillitson E et al (1944) Arylaminoheterocycles. III. Arsenicals of anilinotriazines. J Am Chem Soc 66:1771–1775

    CrossRef  CAS  Google Scholar 

  32. Jonchère H, Gomer J, Reynaud R (1953) Contribution à l'étude de produits à radical mélaminyl dans le traitement de la trypanosomiase humaine. Bull Soc Pathol Exot 46:386–396

    Google Scholar 

  33. Friedheim EAH (1948) Melarsen oxide in the treatment of human African trypanosomiasis. Ann Trop Med 42:357–363

    CAS  Google Scholar 

  34. Peters R, Stocken L, Thompson R (1945) British Anti-Lewisite (BAL). Nature 156:616–619

    CrossRef  CAS  Google Scholar 

  35. Friedheim EAH (1953) Heterocyclic metal and sulfur organic compounds. US Patent 2,664,432

    Google Scholar 

  36. Gibaud S, Alfonsi R, Mutzenhardt P et al (2006) (2-Phenyl-[1, 3, 2] dithiarsolan-4-yl)-methanol derivatives show in vitro antileukemic activity. J Organomet Chem 691:1081–1084

    CrossRef  CAS  Google Scholar 

  37. Friedheim EAH (1952) Propylene glycol solution of arsenic medicaments. US Patent 3,593,434

    Google Scholar 

  38. Watson HJC (1962) Mel W: A field trial in the treatment of Trypanosoma gambiense sleeping sickness. Trans R Soc Trop Med Hyg 56:231–235

    CrossRef  CAS  Google Scholar 

  39. Watson HJC (1965) Mel W: final report on a field trial in the treatment of Trypanosoma gambiense sleeping sickness. Trans R Soc Trop Med Hyg 59:163–170

    CrossRef  CAS  Google Scholar 

  40. Loiseau PM, Lubert P, Wolf JG (2000) Contribution of dithiol ligands to In vitro and In vivo trypanocidal activities of dithiaarsanes and investigation of ligand exchange in an aqueous solution. Antimicrob Agents Chemother 44:2954–2961

    CrossRef  CAS  Google Scholar 

  41. Pépin J, Milord F, Khonde A et al (1994) Gambiense trypanosomiasis: frequency of, and risk factors for, failure of melarsoprol therapy. Trans R Soc Trop Med Hyg 88:447–452

    CrossRef  Google Scholar 

  42. Pépin J, Milord F (1991) African trypanosomiasis and drug-induced encephalopathy: risk factors and pathogenesis. Trans R Soc Trop Med Hyg 85:222–224

    CrossRef  Google Scholar 

  43. Kennedy PGE (2006) Diagnostic and neuropathogenesis issues in human African trypanosomiasis. Int J Parasitol 36:505–512

    CrossRef  CAS  Google Scholar 

  44. Adams JH, Haller L, Boa FY et al (1986) Human African trypanosomiasis (T.b. gambiense): a study of 16 fatal cases of sleeping sickness with some observations on acute reactive arsenical encephalopathy. Neuropathol Appl Neurobiol 12:81–94

    CrossRef  CAS  Google Scholar 

  45. Friedheim EAH (1951) Mel B in the treatment of tryparsamide resistant T. gambiense sleeping sickness: observations on drug resistance in the trypanosomes of the French Cameroon. Am J Trop Med Hyg 31:218–226

    CAS  Google Scholar 

  46. Friedheim EAH (1949) Mel B in the treatment of human trypasonomiasis. Am J Trop Med Hyg 29:173–180

    CAS  Google Scholar 

  47. Burri C, Nkunku S, Merolle A et al (2000) Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. Lancet 355:1419–1425

    CrossRef  CAS  Google Scholar 

  48. Pépin J, Mpia B (2006) Randomized controlled trial of three regimens of melarsoprol in the treatment of Trypanosoma brucei gambiense trypanosomiasis. Trans R Soc Trop Med Hyg 100:437–441

    CrossRef  Google Scholar 

  49. Pépin J, Milord F, Guern C et al (1989) Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet 1:1246–1250

    CrossRef  Google Scholar 

  50. Carter NS, Fairlamb AH (1993) Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 361:173–176

    CrossRef  CAS  Google Scholar 

  51. Balasegaram M, Young H, Chappuis F et al (2009) Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes. Trans R Soc Trop Med Hyg 103:280–290

    CrossRef  CAS  Google Scholar 

  52. Jennings FW (1993) Combination chemotherapy of CNS trypanosomiasis. Acta Trop 54:205–213

    CrossRef  CAS  Google Scholar 

  53. Pépin J, Ethier L, Kazadi C et al (1992) The impact of human immunodeficiency virus infection on the epidemiology and treatment of Trypanosoma brucei gambiense sleeping sickness in Nioki, Zaire. Am J Trop Med Hyg 47:133–140

    Google Scholar 

  54. Kennedy PGE (2008) The continuing problem of human African trypanosomiasis (sleeping sickness). Ann Neurol 64:116–126

    CrossRef  Google Scholar 

  55. Harper K, Ocampo P, Steiner B et al (2008) On the origin of the treponematoses: a phylogenetic approach. PLoS Negl Trop Dis 2:e148

    CrossRef  Google Scholar 

  56. Ehrlich P, Bertheim A (1911) Derivatives of oxyarylarsinic acids and process of making same. US Patent 986,148

    Google Scholar 

  57. Christiansen WG (1920) Hypophosporous acid preparation of arsphenamine. (3, 3-diamino-4, 4-dihydroxy-arseno-benzene dihydrochloride. J Am Chem Soc 42:2402–2405

    CrossRef  CAS  Google Scholar 

  58. Lloyd NC, Morgan HW, Nicholson BK et al (2005) The composition of Ehrlich's Salvarsan: resolution of a century-old debate. Angew Chem Int Ed 44:941–944

    CrossRef  CAS  Google Scholar 

  59. Pariser RJ (2008) Syphilis rules. Clin Dermatol 26:399–410

    CrossRef  Google Scholar 

  60. Anonymous (1911) Salvarsan, new indications. Cal State J Med 9:265–266

    Google Scholar 

  61. Kaufmann SHE (2008) Paul Ehrlich: founder of chemotherapy. Nat Rev Drug Discov 7:373

    CrossRef  CAS  Google Scholar 

  62. Kolmer J, Schamberg J (1912) Experimental studies on the administration of salvarsan by mouth to animals and man. J Exp Med 15:498–509

    CrossRef  CAS  Google Scholar 

  63. Fleming A, Florey HW, Bodenham DC et al (1944) Discussion on penicillin. Proc R Soc Med 37:101–112

    CAS  Google Scholar 

  64. Chain E, Florey HW (1944) Penicillin. Endeavour 3:3–14

    CAS  Google Scholar 

  65. Chain E, Florey HW, Gardner AD et al (1940) Penicillin as a chemotherapeutic agent. Lancet 2:226–228

    CrossRef  Google Scholar 

  66. Florey HW, Chain E (1945) Penicillin: demonstration of its value as a chemotherapeutic agent. Preliminary report of a new method. Med Rec (1866-1922) 158:217–219

    CAS  Google Scholar 

  67. Florey HW (1944) Penicillin: a survey. Br Med J 2:169–170

    CrossRef  CAS  Google Scholar 

  68. Heatley NG (1945) Administration of penicillin by mouth. Lancet 1:590–591

    CrossRef  Google Scholar 

  69. Ehrlich P, Karrer P, Georg Speyer H (1915) Arseno-metallic compounds. Ber Dtsch Chem Ges 48:1634–1644

    CrossRef  CAS  Google Scholar 

  70. Raiziss GW, Kremens A (1926) Arseno-bismuth compound and process of making same. US Patent 1,605,691

    Google Scholar 

  71. Stokes JH, Chambers SO (1927) Bismuth arsphenamine sulphonate. J Am Med Assoc 89:1500

    CrossRef  Google Scholar 

  72. Rayburn CR, Boyd TM (1931) The treatment of neurosyphilis - Observations on 393 patients over a period of five years. Am J Syph 15:168–184

    Google Scholar 

  73. World Health Organisation (1997) Weekly epidemiological record 72:97–100

    Google Scholar 

  74. Gunn H (1918) Amebiasis: its radical cure with combined emetin and salvarsan products. Cal State J Med 16:240–244

    CAS  Google Scholar 

  75. Fourneau E (1925) Relation between chemical constitution and therapeutic action. In: Union Internationale de chimie pure et appliquée (ed.) Comptes rendus de la sixième conférence internationale de la chimie, Bucarest

    Google Scholar 

  76. James DM (1949) The relation between the effect of certain therapeutic agents on infusoria and on pathogenic protozoa. Ann Trop Med Parasitol 43:164–173

    CAS  Google Scholar 

  77. David NA, Anderson HH, Koch DA et al (1932) Comparative toxicity and protozoacidal action of acetarsone, carbarsone and certain related quinquevalent arsenical compounds. Proc Soc Exp Biol Med 29:125–128

    CAS  Google Scholar 

  78. Chopra RN, Sen B, Sen G (1935) Amibiarson in the treatment of chronic intestinal amebiasis. Ind Med Gaz 70:324–328

    CAS  Google Scholar 

  79. Anonymous. (1971) Food additives. Carbarsone (not USP) in combination with bacitracin methylene disalicylate. Fed Regist 36:24001–24002

    Google Scholar 

  80. Schneider J, Dupoux R, Montezin G (1957) Traitement de l'amibiase intestinale par le diphetarsone-spiramycine (6 753 RP). Bull Soc Pathol Exot Filiales 50:600–606

    CAS  Google Scholar 

  81. Elsdondew R, Powell SP, Wilmot AJ (1957) Diphetarsone in the treatment of acute amoebic dysentery. J Trop Med Hyg 60:16–18

    CAS  Google Scholar 

  82. Schneider J, Biguet J, Machez J (1960) Treatment of oxyuriasis by diphetarsone-spiramycin and by diphetarsone. Therapie 15:648–654

    CAS  Google Scholar 

  83. Friedheim EAH (1949) A five day peroral treatment of yaws with stb, a new trivalent arsenical. Am J Trop Med Hyg 29(suppl 1):185

    CAS  Google Scholar 

  84. Anonyme (1953) New and nonofficial remedies; arsthinol. J Am Med Assoc 152:531

    Google Scholar 

  85. Abernathy CO, Liu YP, Longfellow D et al (1999) Arsenic: health effects, mechanisms of actions, and research issues. Environ Health Perspect 107:593–597

    CrossRef  CAS  Google Scholar 

  86. Stohrer G (1991) Arsenic: opportunity for risk assessment. Arch Toxicol 65:525–531

    CrossRef  CAS  Google Scholar 

  87. Cutler E, Bradford E (1878) Action of iron, cod liver oil and arsenic on globular richness of the blood. Am J Med Sci 75:74–84

    CrossRef  Google Scholar 

  88. Stockman R (1898) The action of arsenic on the bone-marrow and blood. J Physiol 23:376–382

    CAS  Google Scholar 

  89. Forkner C, Scott T (1931) Arsenic as a therapeutic agent in chronic myelogenous leukemia. J Am Med Assoc 97:3–5

    CrossRef  Google Scholar 

  90. Rontgen W (1896) On a new kind of rays. Science 3:227–231

    CrossRef  CAS  Google Scholar 

  91. Senn N (1903) Case of spleno-medullary leukemia successfully treated by the use of roentgen ray. Med Rec NY 63:281

    Google Scholar 

  92. Wang ZY (2001) Arsenic compounds as anticancer agents. Cancer Chemother Pharmacol 48(suppl 1):S72–S76

    CrossRef  CAS  Google Scholar 

  93. Sun HD, Li H, Ma L et al (1992) Treatment of acute promyelocytic leukemia by Ailing-1 therapy (in Chinese). Chin J Integr Trad Med West Med 12:170–172

    Google Scholar 

  94. Zhang P, Wang SY, Lu LH et al (1996) Arsenic trioxide-treated 72 cases of acute promyelocytic leukemia (in Chinese). Clin J Hematol 17:58–62

    Google Scholar 

  95. Lu DP, Qiu JY, Jiang B et al (2002) Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report. Blood 99:3136–3143

    CrossRef  CAS  Google Scholar 

  96. Soignet SL, Tong WP, Hirschfeld S et al (1999) Clinical study of an organic arsenical, melarsoprol, in patients with advanced leukemia. Cancer Chemother Pharmacol 44:417–421

    CrossRef  CAS  Google Scholar 

  97. Soignet SL, Maslak P, Wang ZG et al (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339:1341–1348

    CrossRef  CAS  Google Scholar 

  98. Warrell R, Soignet S, Maslak P et al (1998) Initial western study of arsenic trioxide (As2O3) in acute promyelocytic leukemia (APL). Proc Am Soc Clin Oncol 17:6a

    Google Scholar 

  99. Chen GQ, Zhu J, Shi XG et al (1996) In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML- RARα/PML proteins. Blood 88:1052–1061

    CAS  Google Scholar 

  100. Dai J, Weinberg RS, Waxman S et al (1999) Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 93:268–277

    CAS  Google Scholar 

  101. Jing Y, Dai J, Chalmers-Redman RME et al (1999) Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 94:2102–2111

    CAS  Google Scholar 

  102. Schmidt A, Koppelt J, Neustadt M et al (2007) Mass spectrometric evidence for different complexes of peptides and proteins with arsenic (III), arsenic (V), copper (II), and zinc (II) species. Rapid Commun Mass Spectrom 21:153–163

    CrossRef  CAS  Google Scholar 

  103. Rousselot P, Labaume S, Marolleau JP et al (1999) Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. Cancer Res 59:1041–1048

    CAS  Google Scholar 

  104. Wang ZG, Rivi R, Delva L et al (1998) Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in a PML and PML-RARalpha independent manner. Blood 92:1497–1504

    CAS  Google Scholar 

  105. Konig A, Wrazel L, Warrell RP et al (1997) Comparative activity of melarsoprol and arsenic trioxide in chronic B- cell leukemia lines. Blood 90:562–570

    CAS  Google Scholar 

  106. De Los SJ, Thomas G (2007) Anemia correction in malignancy management: threat or opportunity? Gynecol Oncol 105:517–529

    CrossRef  Google Scholar 

Download references

Acknowledgments

The authors are thankful to Miss Amy Jones (University of Glasgow) for improving the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stéphane Gibaud .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Gibaud, S., Jaouen, G. (2010). Arsenic-Based Drugs: From Fowler’s Solution to Modern Anticancer Chemotherapy. In: Jaouen, G., Metzler-Nolte, N. (eds) Medicinal Organometallic Chemistry. Topics in Organometallic Chemistry, vol 32. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-13185-1_1

Download citation