By Dr Ananya Mandal, MD
Chemotherapy was first developed at the beginning of the 20th century, although it was not originally intended as a cancer treatment.
During World War II, it was discovered that people exposed to nitrogen mustard developed significantly reduced white blood cell counts. This finding led researchers to investigate whether mustard agents could be used to halt the growth of rapidly dividing cells such as cancer cells.
In the 1940s, two prominent Yale pharmacologists, Alfred Gilman and Louis Goodman examined the therapeutic effects of mustard agents in treating lymphoma. First, they established lymphomas in mice and showed that the tumors could be treated with mustard agents. Then, together with a thoracic surgeon called Gustav Linskog, they injected a less volatile form of mustard gas called mustine (nitrogen mustard) into a patient who had nonHodgkin's lymphoma.
The scientists found that the patients tumour masses were significantly reduced for a few weeks after treatment and although the patient had to return to receive more chemotherapy, this marked the beginning of the use of cytotoxic agents for the treatment of cancer. The initial study was done in 1943 and the results were published in 1946.
The use of nitrogen mustard for lymphomas gained popularity in the United States after the publication of the article in 1946. Nitrogen mustard and other derivatives of mustard gas are called alkylating agent due to their ability to alkylate molecules including protein, DNA and RNA. Other examples of alkylating agents include the tetrazines and the cisplatins.
After World War II, another chemotherapeutic approach was investigated. A pathologist from Harvard Medical School called Sidney Farber studied the anticancer effects of folic acid - an essential vitamin in DNA metabolism.
Faber and colleagues developed folate analogues (such as methotrexate) which they found were antagonistic to folic acid and prevented the action of enzymes that required folate. In 1948, these agents became the first to lead to remission in children with acute lymphoblastic leukemia, showing that antifolates had the potential to restore normal bone marrow.
In the 1950s, Eli Lilly and company announced that plant alkaloids such as those extracted from Vinca rosea were beneficial to leukemia patients. This led to the introduction of vinca alkaloids as anticancer agents in the 1960s. Examples include vinblastine used to treat Hodgkin's disease and vincristine used to treat pediatric leukemia.
Over the next two decades, combination chemotherapy regimens started to gain popularity. The concurrent use of drugs with different mechanisms of action led to further improvements in patient survival and to a decline in mortality rates, which have declined each year from 1990 until now. This fall in death rates is due to both early detection and treatment with chemotherapy agents.
Reviewed by Sally Robertson, BSc