Today, cancer is used as an umbrella term for a group of about 120 different diseases that can affect any part of the body and are defined as a condition characterized by uncontrolled growth, invading normal tissues, and the spread of cells. According to the reports of the WHO, cancer cases are expected to increase to 21 million by 2030, despite progress in prevention, early detection, and treatment. Modern cancer therapy combines surgery, radiotherapy, chemotherapy, hormonal therapy, and immunotherapy. When cancer has metastasized, chemotherapy using natural or synthetic anticancer drugs is available. Anticancer drug discovery has gone from random discovery to strategic design based on chemical, physical, and biological advances.
In this article, we will read about some ‘Happy Accidents’ in the discovery of anticancer drugs that have given a new direction to cancer treatment.
Cisplatin:
Cisplatin is called the ‘penicillin of cancer’ because of its widespread use as a potent chemotherapy drug. Biophysical chemist Barnett Rosenberg accidentally discovered it as an anti-cancer drug.
In 1965, American physicist Barnett Rosenberg and microbiologist Loretta Van Camp wanted to find out if electric fields affected the growth of the Escherichia coli bacteria. So they dipped the metal electrodes into the bacteria's nutrient broth. They noticed that the bacteria stopped dividing when placed in an electric field, but the size of the bacteria increased 300 times. But after much agonizing and head-scratching, it turned out that the cause had nothing to do with electricity. Instead, the effect was caused by the electrodes they used, which were made of a metal called platinum, which corroded in the test solution, producing 'Cisplatin.'
This raised an interesting question: If platinum can stop the cell division of fast-growing bacteria, can it similarly stop tumor cell growth? This astonishing discovery was later transformed into the development of cisplatin, the first platinum-based cancer medicine, by these curious minds.
Cisplatin has been used to treat cancer since it was approved by the US Food and Drug Administration in 1978. New formulations are being developed to make it more effective and less toxic.
Mustine:
Chemotherapy for cancer had dark origins; it was born from mustard gas, a deadly chemical weapon used during the war. However, it took an unexpected turn when scientists discovered its potential to kill cancer cells, leading to a new boom in cancer treatment.
During World War II, nitrogen mustard was used against the enemy as a chemical warfare agent, and it was observed that the white blood cell count of people exposed to it decreased significantly. This finding prompted researchers to investigate whether mustard substances could be used to stop the growth of rapidly dividing cells, such as cancer cells.
During the 1940s, Alfred Gilman, a Yale pharmacist, and Louis Goodman, another Yale pharmacist, studied the therapeutic properties of mustard gas agents for treating lymphoma. First, they detected lymphomas in mice and showed that the tumors could be treated with mustard gas substances. Together with thoracic surgeon Linskog, they gave a patient an injection of a less volatile mustard gas called ‘Mustine’ (nitrogen mustard), which is used to treat non-Hodgkin’s lymphoma. The researchers found that the patient's tumor mass shrank significantly within weeks of treatment, and although the patient had to return for additional chemotherapy, it marked the beginning of the use of cytotoxic agents in cancer treatment. The first research was carried out in 1943 and published in 1946.
It may come as a surprise or even a source of concern to us that chemical weapons and cancer treatment are related. However, for the doctors and medical scientists of the time, it was a logical result of their wartime mustard gas research. The use of mustine to treat lymphoma became popular in the US after an article was published in 1946.
Vinblastine:
Eli Lilly's (a drug company) discovery of insulin in the early 20th century was a major breakthrough in the treatment of diabetes, but its high potency and the body's resistance to it led to the search for new lead compounds. During this hunt, the Madagascar Periwinkle came into the limelight in the 1950s.
Madagascar Periwinkle (Catharanthus roseus) is a small perennial and ornamental plant native to the island of Madagascar. Infusions made from the leaves of Madagascar Periwinkle have long been used by medicinal healers in various regions, including India, the Philippines, and South Africa, to treat a number of ailments, especially diabetes.
Two research groups (one from Eli Lilly and the other from the University of Western Ontario) independently tested plant extracts to discover new drugs for diabetes. And they had a surprise.
Although the plant extracts did not lower the blood sugar in the mice, they dramatically reduced the number of white blood cells in the blood. Researchers quickly discovered that Madagascar Periwinkle extracts may contain a chemical (or chemicals) with potential anticancer properties as certain types of cancers (like leukemia) cause an increase in white blood cells.
Dr. Robert Noble of the University of Western Ontario and Eli Lilly's researchers collaborated to develop ‘Vinblastine’ from the periwinkle extract.
In the 1960s, the US Food and Drug Administration approved vinblastine as a chemotherapeutic agent for the treatment of several cancers. Since then, vinblastine, a powerful inhibitor of cell division, has been used with other chemotherapy drugs to treat lymphoma, as well as testicular, ovarian, breast, bladder, and lung cancers.
Methotrexate:
Methotrexate is an antifolate drug, which means it prevents the activation of folic acid in the body. Most people associate the story of methotrexate (MTX) with scientists with names like Farber or Gubner.
But the history of methotrexate begins a few years earlier. In 1945, Yellapragada Subba Rao, an American scientist of Indian origin, isolated folic acid from the liver for the first time.
In the same year, Subba Rao and his team discovered a microbial source of folic acid and administered it to mice with tumors, leading to tumor regression. But the compound injected was found to be a folic acid antagonist that disturbed DNA synthesis and caused tumor regression.
Encouraged by this, Farber organized a rapid clinical trial in leukemia patients in which he administered folic acid. The results were disastrous due to accelerated tumor growth. But this accidental blunder helped Farber confirm the hypothesis that a lack of folic acid in tumor cells causes their growth to be inhibited.
Farber encouraged Subba Rao to further research and successfully treated acute leukemia in children with a new molecule, aminopterin, which inhibits folic acid synthesis. Subba Rao synthesized aminopterin. The aminopterin molecule turns out to be rather unstable and difficult to synthesize. Thus, the amethopterin analog becomes a star, later called Methotrexate. Farber published the results in his 1948 paper.
In 1951, Gubner et al. found that 86% of rheumatoid arthritis patients treated with methotrexate relapsed after discontinuation. Despite all its serious side effects, methotrexate received FDA approval in 1972 for the treatment of psoriasis and rheumatoid arthritis in 1988.
Methotrexate is still used in high doses intravenously to treat cancer. However, it is currently most commonly used for rheumatoid arthritis and other inflammatory conditions.
The process of searching for new drugs is indeed laborious, time-consuming, and expensive. Regardless of the approach taken for drug discovery, chance discoveries frequently play a role in the process.
References:
https://theconversation.com/happy-50th-anniversary-to-cisplatin-the-drug-that-changed-cancer-treatment-38382
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325736/#:~:text=By%20World%20War%20II%2C%20at,new%20form%20of%20cancer%20treatment.
https://www.jic.ac.uk/blog/vinblastine-and-vincristine-life-saving-drugs-from-a-periwinkle/
https://theconversation.com/weekly-dose-methotrexate-the-anti-inflammatory-drug-that-can-kill-if-taken-daily-60322
http://revistamedicinamilitara.ro/wp-content/uploads/2023/01/RJMM-vol-CXXVI-nr-1-din-2023-part-1.pdf