The introduction of ‘chemotherapy’ using arsphenamine – the first magic bullet

In the late 19th century, Paul Ehrlich (1854–1915) developed an early interest in the specific staining of tissues with dyes, first with methylene blue and then with trypan red and atoxyl. He reasoned this might allow the detection of a substance that would specifically bind to and kill microbes without harming human cells. After working initially under Robert Koch in Berlin, Ehrlich moved to his own institute in Frankfurt (Main). After it had been shown in 1905 that atoxyl, an arsenical, had some activity against trypanosomes, his chemists, led by Alfred Bertheim, synthesized a series of arsenical derivatives. Over this period Ehrlich developed a close relationship with Professor August Laubenheimer, who had joined the pharmaceutical arm of the Meister, Lucius and Bruening dyeworks, now better known by their location (Hoechst). Ehrlich’s work expanded in 1906 after he moved his laboratory into the Georg Speyer Haus, near Frankfurt, close to the dye factories. There were some partial successes, for example, compound 418 (arsenophenylglycine), which was tested clinically by the dermatologist Alfred Neisser (whose name we now associate with the gonococcus). Compound 418 also had some activity when tested in Africa against trypanosomes, which cause sleeping sickness, but it was not as powerful as atoxyl. Ehrlich was looking for an agent that could achieve sterile cultures in animals with a single dose. He coined the terms ‘chemotherapy’ and ‘magic bullet’ to characterize the processes he had in mind. He first used the term ‘magic bullet’ at a Harben Lecture in London in 1908, although the concept (Zauberkugel) had appeared earlier in his writings in German. Syphilis was a scourge affecting a significant proportion of men and women in the early 20th century. Routine therapy for the disease had been with mercury, both as an ointment and internally, but this was quite toxic. In 1905, Fritz Schaudinn and Erich Hoffmann identified the causative organism of syphilis – a spirochaete – which belonged to the same group of organisms as the trypanosomes. So it was that another arsenical – diamino dihydroxy arsenobenzol (arsphenamine) – was discovered, synthesized in 1907 by Alfred Bertheim, and tested on spirochaetes by Ehrlich’s assistants. The two assistants who first tested it concluded that it was useless, and it was therefore put aside until Ehrlich asked his Japanese assistant, Sahashiro Hata, to repeat the experiments. Hata found that arsphenamine was superior to all the other drugs that had been tested, prompting Ehrlich’s fury that the inadequate methods used by his former assistants had resulted in the delay in this discovery. Arsphenamine was known first by the number 606, as the 606th preparation tested in Ehrlich’s laboratory, and subsequently by its trade name Salvarsan when it was marketed in 1910. Ehrlich continued to evaluate further compounds and improved upon Salvarsan with compound 914, Neosalvarsan, which was more soluble and had a lower arsenical content and appeared more active.