chemotherapy

chemotherapy — broadly speaking, the treatment of disease by chemical means — has had a number of different meanings since Paul Ehrlich (1854–1915) first coined the word in 1907. Then the word referred to the treatment of infectious disease by drugs that killed the infective organism, but left the patient unaffected. This led Ehrlich to postulate the concept he called the ‘magic bullet’ — a medicine that would knock out a precise target, leaving other tissues unharmed. At the beginning of the twenty-first century ‘chemotherapy’ is more usually used to refer to treatment of cancer by powerful chemicals — again based on the original premise of Ehrlich's, that powerful medicinal agents will kill cancerous cells in the body, whilst leaving surrounding cells functioning healthily. In between times, the word gained some currency for the drug treatment of any disease condition.

In the final decades of the nineteenth century, Ehrlich was working on the effects of artificial dyes on living cells, in particular trying to stain parasites in animal tissues. In 1891 he discovered that methylene blue would selectively stain the malaria parasite, which indicated to him that the dyes had combined with some specific receptor sites on the parasite, which might provide a mechanism for treating the disease. By administering the dye to patients with malaria, he showed that this could indeed be used therapeutically in humans; a few years later he found that the dye trypan red showed specific activity against trypanosome infections in mice, although it was not therapeutically effective against trypanosome infections in cattle or humans. From these studies he developed a theory that associated the chemical structure of a synthetic drug with its biological effects. In 1909 he discovered the drug Salvarsan, an arsenical compound that was the first effective drug against the organism that causes syphilis, and he used the word ‘chemotherapy’ to indicate the use of such drugs.

In the early 1930s another chemical agent, Prontosil Red, was discovered, which was shown to be an extremely effective treatment against a number of bacterial infections, including erysipelas, streptococcal angina, and puerperal sepsis. Further chemical research on the compound revealed that Prontosil Red was composed of biologically active and inactive parts, the active component being a readily available chemical, a sulphonamide derivative called sulphanilimide. This was an important discovery: on the one hand, it encouraged chemists to explore the molecular structures of biologically active chenicals, and in particular opened up the sulphonamide molecule to much chemical modification; on the other hand, sulphanilimide was a simple chemical, easy and cheap to prepare, and free from patent restrictions. Its production and use became widespread, as did the use of its derivatives, and the sulphonamides soon provided effective treatments for a wide range of conditions caused by Streptococcus bacteria, including some forms of pneumonia and meningitis. Infections caused by Staphylococcus bacteria, however, such as endocarditis and cellulitis, were resistant to sulphonamides.

The discovery of penicillin in 1928 by the bacteriologist Alexander Fleming (1881–1955), and more importantly, its later effective development by a team in Oxford led by the pathologist Howard Florey (1898–1968) and the chemist Ernst Chain (1906–79), opened up, in the 1940s, a new field of chemotherapy called anti-biosis. This was the use of one microorganism, in this case a mould called Penicillium, to destroy another, such as a disease-causing bacterium. The successful chemical isolation and preparation of the active agent produced by the mould led to the use of the drug during World War II, especially for the treatment of wounded or VD-infected soldiers. Scientifically, the discovery of penicillin stimulated much chemical research to find similar agents — this involved massive screening programmes of a wide range of microorganisms, undertaken by institutes and pharmaceutical companies around the world. It also promoted the further investigation of how penicillin killed bacteria, which was by interfering with the manufacture of the bacterial cell wall. This in turn encouraged research work to find other compounds with the same effect. Gradually, synthetic chemicals were manufactured, which did not therefore fit the precise description of ‘antibiotics’, as they were not produced by microorganisms, although the expression ‘antibiotics’ has continued to be applied to all these medicinal drugs. These antibiotics, whether produced by living organisms, such as mould and fungi, or whether created synthetically in a laboratory, revolutionized the treatment of most infectious diseases. Unfortunately their widespread use has also caused problems, as pathogenic microorganisms are increasingly developing resistance to the powerful drugs designed to kill them. As yet, similar drugs to counteract viral caused diseases have not been produced.

The discovery of the sulphonamide family of drugs in the 1930s coincided with a short period when the word ‘chemotherapy’ was often used to indicate the treatment of any disease with a therapeutic chemical. Thus most modern drug therapy can be regarded, in one sense, as ‘chemotherapy’. Increasingly, however, the word has come to be used now in association with cancer therapies, cancer chemotherapy having the same connotation as the original usage in infectious conditions — the therapeutic agent will destroy the malignancy without affecting surrounding healthy cells and tissues.

Cytotoxic drugs, which destroy rapidly-proliferating cells such as those found in tumours, started being developed, particularly after World War II, especially in the US. Early trials, on diseases such as childhood leukaemia and Hodgkin's disease, were discouraging, the toxic chemicals used almost invariably proving poisonous not only to the cancerous cells but also to normal, unaffected cells. More advanced developments have produced drugs that are effective against a number of cancers, including some that are effective against cancer cells throughout the body, and so can attack cancerous cells that have spread. Several different types of drugs have been developed — alkylating agents, for example, inhibit cell division, whilst anti-metabolites interfere with enzyme systems and block vital processes. These drugs, however, are not readily able to distinguish between healthy and infected cells, and supplementary therapies to protect normal cells and tissues are also given. The concomitant development of drugs to counteract some of the distressing side effects of these powerful medicines, such as nausea and vomiting, hair loss, and fatigue, have also contributed to the success and acceptability of much modern chemotherapy. New fields of research, especially stimulated by developments in understanding the genetic and molecular mechanisms of cancer, have opened up a number of new therapeutic strategies.

E. M. Tansey

See also cancer; infectious diseases.