CHEMOTHERAPY

the treatment of diseases by chemical compounds. Chemotherapeutic drugs were originally those employed against infectious microbes, but the term has been broadened to include anticancer and other drugs. Until the end of the 19th century, most drugs were derived either from minerals or from plants. The researches of Louis Pasteur in France and Robert Koch in Germany laid the foundations of bacteriology. It was Paul Ehrlich, however, who made the greatest contribution to the science (chemotherapy) he named. The problem facing medical scientists was to produce a disinfectant that would destroy parasites within a living animal without serious damage to the host. William H. Perkin, in England, made the first aniline dye (1856) as a result of abortive attempts to synthesize quinine, the sole antimalarial drug available at that time. About 30 years later, Ehrlich found that a synthetic dye, methylene blue, has antimalarial properties. He had been led to this by a study of the specific staining of organs of an animal or of a parasite following the injection of a synthetic dye. From these studies there emerged (1901-04) Ehrlich's well-known "side-chain" theory, in which he sought for the first time to correlate the chemical structure of a synthetic drug with its biological effects. In 1903 Ehrlich invented a dye, trypan red, which was the first drug to show activity against trypanosomal infections in mice. Ehrlich's greatest triumph, however, was the discovery (1910) of the organic arsenical drug Salvarsan, which proved to be effective in the treatment of syphilis. The discovery of other chemotherapeutic agents followed, including mepacrine, proguanil, and chloroquine. The discovery of Prontosil in the early 1930s proved that antibacterial agents could be developed. Prontosil was the forerunner of the sulfonamide drugs, which came to be widely used for the treatment of bacterial infections in humans and domestic animals. The discovery of penicillin by Sir Alexander Fleming in 1928, and its practical development by Sir Howard Florey and Ernst Chain, marked another important advance in bacterial chemotherapy. Penicillin, which did not become widely used until World War II, was the first of the so-called antibiotics, and it was followed by other important antibiotics such as streptomycin, the tetracyclines, and the macrolides. Antibiotics, whether they are produced by living organisms (usually fungi or bacteria) or artificially synthesized, have transformed the modern management of diseases caused by bacteria and most other microorganisms. Paradoxically, the more widely they are used, the greater the likelihood that drug-resistant bacteria will emerge. Bacteria may develop resistance to drugs in several ways: mutation changes in genetic composition; transduction, whereby resistance is transferred from a resistant to a nonresistant strain; transformation, in which a bacterial cell takes from its environment the genes from a resistant form to acquire resistance; and conjugation, in which the organism acquires resistance by cell-to-cell contact. Another comparative failure of chemotherapy is the lack of drugs to combat viruses (although viral infections can be controlled through prophylactic measures). Drug modes of action vary. For example, some may act on the bacterial wall, others affect cell membranes, some modify the molecular mechanism for duplication, some change the nucleic acid metabolism, and others change the intermediary metabolism of two interacting organisms. Cancer chemotherapy is an increasingly important aspect of drug treatment. Alkylating agents (that work by impairing cell division) and antimetabolites (that interfere with enzymes and thus block vital cell processes) are used cytotoxically to attack malignant cells. Steroid hormones are used in the treatment of breast and prostate cancers, and corticosteroids are used to treat leukemia and lymphatic cancers. The periwinkle plant derivatives vincristine and vinblastine have been used effectively in treating Hodgkin's disease and leukemia. The alkylating agents and antimetabolites have serious drawbacks. As they cannot distinguish between healthy and malignant cells, these drugs also interfere with actively multiplying noncancerous cells. They also reduce the body's resistance to infection. Work is being done on tumour-specific agents that attack only cancer cells. Another area where chemotherapy has had a major, albeit controversial, impact is mental illness. Severe depression, anxiety, and schizophrenia are now treated with various drugs. Concomitant with the successes of drug therapy has come increasing concern about attendant dangers. Stringent controls are operated by such regulatory agencies as the Food and Drug Administration in the United States and the Committee on Safety of Medicines in the United Kingdom. These bodies ensure the safety of pharmaceuticals before they are placed on the market and monitor any side effects thereafter. Public demands for "watchdog" agencies were triggered in large part by the 1962 Thalidomide tragedy, when thousands of severely deformed children were born to users of that insufficiently tested drug.