The history of chemotherapy goes back to the 1940s when nitrogen mustards and folic acid were first used as antagonist drugs. Today, cancer drug development is a multi-billion dollar industry. The targeted therapy revolution has arrived and many other drugs are still under clinical research. However, the principles and limitations of chemotherapy discovered by the early researchers still hold true.

Nitrogen mustard was used as a chemical warfare agent, was later discovered as an effective treatment for cancer. Two pharmacologists were recruited by the United States Department of Defense to investigate therapeutic applications of chemical warfare agents. During that time, a raid led to the exposure of more than one thousand people to the secret cargo composed of mustard gas bombs. A Lieutenant Colonel and an expert in chemical warfare, investigated the aftermath of this exposure. Autopsies of the victims were carried out and they found that lymphoid and myeloid suppression in the cells occurred after exposure. This led to the discovery that mustard gas stopped the division of certain types of cells especially the ones, which divide fast. This led to the use of nitrogen mustard to suppress growth of the cancer cells.

The two pharmacologists reasoned that this agent could be used in the treatment for lymphoma cancer since it is a tumor of lymphoid cells. They experimented this on mice.
Later, with the help of a thoracic surgeon, they injected mustine, which is a prototype of nitrogen mustard into the patient of non-Hodgkin lymphoma. They observed a reduction in the tumor. Although, that lasted only for a few weeks and the treatment had to be repeated, they realized that cancer could be treated with the help of pharmacological agents.

After the Second World War, a new approach was developed. A pathologist in Harvard studied the effects of folic acid on leukemia patients. Lucy Wills discovered that folic acid stimulated the proliferation of acute lymphoblastic leukemia (ALL) cells.

In collaboration with Lederle Laboratories, folate analogues- aminopterin and amethopterin (now known as methotrexate) were used and found antagonistic to folic acid. They blocked the function of folate-requiring enzymes. These became the first drugs to bring reduction in tumors in ALL cases. These were brief; however, it was discovered that antifolates could suppress proliferation of malignant cells and re-establish bone-marrow function.

Later, at the National Cancer Institute, it was discovered that the same methotrexate treatment could cure choriocarcinoma. This was the first big tumor cured by chemotherapy.

Methotrexate was studied further and by making some changes in the metabolite required for cell division, new anti metabolites were developed. The analogues were tested that led to the discovery of 6-mercaptopurine (6-MP) which is a drug used to treat leukemia.

Later Ely Lilly discovered that alkaloids Vinca rosea, suppressed the proliferation of tumor cells. Vincristine was developed which has the ability to inhibit microtubule polymerization and thus cell division.

In a major break-through, it was discovered in 1965 that combination of drugs should be used each with a different mechanism as cancer cells could become resistant to a single agent. Hence, methotrexate-an antifolates and, vincristine a Vinca alkaloid were administered together. 6-mercaptopurine (6-MP) and prednisone were administered as a dose of chemotherapy for children together to treat children with ALL. There were refinements done and with a lot of clinical research, ALL in children is now a curable disease.

Later in 1963, MOPP regimen was discovered i.e. the use of nitrogen mustard, vincristine, procarbazine and prednisone. This could cure patients with Hodgkin’s and non-Hodgkin’s lymphoma. These drugs are still highly successful.

Later, adjuvant therapy was discovered i.e. if the tumor could be first removed by surgery and then treated with chemotherapy; the result could be more effective.

History of chemotherapy began around seventy years ago. Today, molecular and genetic approaches to understanding cell biology have discovered links that regulate cellular activities like proliferation and survival. These cellular activities are radically altered in cancer cells and are caused by mutations.