<P> The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs . The targeted therapy revolution had arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply . </P> <P> The beginnings of the modern era of cancer chemotherapy can be traced directly to the German introduction of chemical warfare during World War I. Among the chemical agents used, mustard gas was particularly devastating . Although banned by the Geneva Protocol in 1925, the advent of World War II caused concerns over the possible re-introduction of chemical warfare . Such concerns led to the discovery of nitrogen mustard, a chemical warfare agent, as an effective treatment for cancer . Two pharmacologists from the Yale School of Medicine, Louis S. Goodman and Alfred Gilman, were recruited by the US Department of Defense to investigate potential therapeutic applications of chemical warfare agents . Goodman and Gilman observed that mustard gas was too volatile an agent to be suitable for laboratory experiments . They exchanged a nitrogen molecule for sulfur and had a more stable compound in nitrogen mustard . A year into the start of their research, a German air raid in Bari, Italy led to the exposure of more than 1000 people to the SS John Harvey's secret cargo composed of mustard gas bombs . Dr. Stewart Francis Alexander, a lieutenant colonel who was an expert in chemical warfare, was subsequently deployed to investigate the aftermath . Autopsies of the victims suggested that profound lymphoid and myeloid suppression had occurred after exposure . In his report, Dr. Alexander theorized that since mustard gas all but ceased the division of certain types of somatic cells whose nature was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells . </P> <P> Using that information, Goodman and Gilman reasoned that this agent could be used to treat lymphoma, a tumor of lymphoid cells . They first set up an animal model by establishing lymphomas in mice and demonstrated they could treat them with mustard agents . Next, in collaboration with a thoracic surgeon, Gustaf Lindskog, they injected a related agent, mustine (the prototype nitrogen mustard anticancer chemotherapeutic), into a patient with non-Hodgkin's lymphoma . They observed a dramatic reduction in the patient's tumor masses . Although the effect lasted only a few weeks, and the patient had to return for another set of treatment, that was the first step to the realization that cancer could be treated by pharmacological agents . Publication of the first clinical trials was reported in the New York Times . </P> <P> Shortly after World War II, a second approach to drug therapy of cancer began . Sidney Farber, a pathologist at Harvard Medical School, studied the effects of folic acid on leukemia patients . Folic acid, a vitamin crucial for DNA metabolism (he did not know the significance of DNA at that time), had been discovered by Lucy Wills, when she was working in India, in 1937 . It seemed to stimulate the proliferation of acute lymphoblastic leukemia (ALL) cells when administered to children with this cancer . In one of the first examples of rational drug design (rather than accidental discovery), Farber used folate analogues synthesized by Harriett Kilte and Yellapragada Subbarow of Lederle Laboratories . These analogues--first aminopterin and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate - requiring enzymes . When administered to children with ALL in 1948, these agents became the first drugs to induce remission in children with ALL . Remissions were brief, but the principle was clear--antifolates could suppress proliferation of malignant cells, and could thereby re-establish normal bone - marrow function . Farber met resistance to conducting his studies at a time when the commonly held medical belief was that leukemia was incurable, and that the children should be allowed to die in peace . Afterwards, Farber's 1948 report in the New England Journal of Medicine was met with incredulity and ridicule . </P>

When was chemotherapy first used in the uk