Fifty years of chemotherapy In the material sense, the pattern of western civilisation is now determined by science-based industry: technology is the most formative factor in modern life. Whether this is a good thing or not is a matter for continuing, and no doubt continuous, debate between those who regard technology as an unmixed blessing and those of the back-to-nature movement who see it as a near-catastrophe. Even between extremists, however, there is a measure of common ground and on the whole it is regarded as a matter for satisfaction that people live longer and healthier lives: even so, some prophets of doom seek to persuade us that this simply over-taxes the worlds limited resources and thus only leads to more trouble in the long run.
Nevertheless, the consensus of opinion is that the conquest of disease is a laudable aim and that success is praiseworthy. It is appropriate, therefore, to commemorate the fiftieth anniversary of a major medical event, Gerhard Domagks discovery of the antibacterial properties of Prontosil Red in 1932, for this was the first of a series of events which have literally transformed the medical scene. Medical students today see few cases of the serious and commonly fatal or seriously disabling bacterial infections which were distressingly commonplace in the 1930s: among them bacterial pneumonia and meningitis, puerperal fever, congenital syphilis, and mastoid infections.
In the latter part of the nineteenth century it was widely believed that the vital processes of all living cells had so much in common that it was futile to seek a chemical agent that would distinguish one from the other-a substance that could be administered systemically to destroy invading bacteria but would be harmless to the cells of the human body. As is well known, one of those who questioned this defeatist view was Paul Ehrlich, who after several hundred trials introduced his compound 606 (Salvarsan) for the treatment of human syphilis in 1911. Salvarsan, an arsenical, was not an ideal drug and had unpleasant side effects: nevertheless, it not only represented a substantial advance in the treatment of syphilis but established the possibility of a magic bullet that would distinguish between pathogenic organisms and human cells. Ehrlich felt justified in coining the word chemotherapy to describe this form of treatment.
In 1927 the I.G. Farbenindustrie, then the worlds leading chemical company, decided-as a speculative venture-to initiate, under Domagk, a long-term search for new chemotherapeutic agents. It involved three phases: the identification of substances with high activity against pathogenic bacteria; determination of their toxicity; and finally testing them against infection in experimental animals. At that time there were no real guides to follow. The best that could be done was to screen a very large number of chemicals in the hope of finding something useful: it was part of the I.G.s strength that its laboratories were a virtually endless source of supply. It is salutary to reflect that even today this screening process is about the best we can do in the search for new classes of biologically active substances: we are only just beginning to relate structure to properties. Not until 1932 was any significant success achieved. In that year Domagk
received a sample of Prontosil Red, a new dye intended for use with leather. This passed preliminary tests as regards activity and toxicity, and later was spectacularly successful in protecting mice which had received lethal doses of haemolytic streptococci. For reasons which have never been satisfactorily explained these important results were not published until 1935. A widely accepted explanation is that difficulties were encountered in repeating this early success. Another, and more plausible, one is that I.G. chemists quickly discovered that the antibacterial activity was not a property of the whole Prontosil molecule but of the sulphanilamide moiety of it: as sulphanilamide had been prepared by the Austrian chemist Paul Gelmo in 1908 it could not be patented. They therefore devoted a great deal of time to preparing patentable variants of sulphanilamide suitable for chemotherapy, but without success. Two circumstances lend colour to this view. Firstly, when the results were finally published in 1935 J. Trefougl of the Pasteur Institute in Paris soon showed that sulphanilamide was the active principle: what he could do so quickly the I.G. chemists could surely have done for themselves. Secondly, Trefou&ls announcement led to worldwide research to ring the chemical changes on sulphanilamide. By 1942 nearly 4000 related substances had been investigated but only four-sulphapyridine (1938); sulphaguanidine and sulphathiazole (1940); and sulphadiazine (1941)-had warranted development. It is not surprising, therefore, that I.G. had no quick success in this search.
The immediate consequences were dramatic: in an early trial at Queen Charlottes Hospital in London, for example, mortality for puerperal fever was reduced from 20 to 5 per cent. When these results were published in The Lancet, an editorial comment urged readers to treat them with caution. Caution was not necessary, however: extended trials fully confirmed early optimism and a new era in chemotherapy began.
The long-term consequences were also important. The advent of the sulphonamides finally established the possibility of differential activity between bacterial and human cells, and created a new climate of thought. This was a factor in the decision by Howard Florey and Ernst Chain in 1939 to make an inves- tigation of penicillin, which Alexander Fleming had abandoned after his discovery of it ten years earlier, before the advent of sulphanilamide. The spectacular demonstration of the unique chemotherapeutic properties of penicillin by the Oxford workers; its dramatic wartime development for the treatment of wounds; and its subsequent universal introduction into medical practice needs no retelling, for penicillin is now commonly referred to as a conventional drug. From penicillin stemmed other valuable agents- including the semisynthetic penicillins and the cephalosporins and their derivatives.
It is true that the prolongation of human life effected by developments in chemotherapy in the past fifty years has contributed substantially to the population explosion of recent years and all its attendant problems. Nevertheless, it would surely be hard to find advocates for a return to the situation of fifty years ago, when most generalized bacterial infections were a cause for despair.