What is the best hope for cancer patients?
is a new anticancer drug on the market!
But few people know how hard it is for scientists to discover a new cancer drug! Let us approach these great “drug hunters” in history together and uncover the twists and turns behind the discovery of anticancer drugs.
In the history of human beings fighting against tumors, chemotherapy is the earliest and most widely used weapon for human beings. Commonly used drugs include cisplatin, paclitaxel, 5-fluorouracil, cyclophosphamide and Bendamustine, etc.
These drugs are highly cytotoxic and can kill rapidly dividing cells.
So, who first discovered chemotherapy drugs? No one could have imagined that the opening of the “era of cancer chemotherapy” was actually related to a chemical weapons disaster.
(German bombing of the port of Bari, Italy. Source: history)
In December 1943, the German bombing of the port of Bari, Italy, sank 17 transport ships and cargo ships, including an American ship named “John Harvey” secretly loaded 2,000 mustard gas bombs. The bombing by the Luftwaffe, which resulted in the release of toxic mustard gas and a thick, sulphur-coloured fog that blanketed the port, poisoned 617 people, 83 of whom died within a week[1].
Despite strong denials by British authorities of the existence of mustard gas bombs, Stuart Francis Alexander, an American chemical weapons expert who went to investigate, quickly diagnosed the cases as mustard gas poisoning. In his top-secret document, “Final Report on Barry Mustard Gas Casualties,” he details the initial survivors of the blast. More than a thousand people died of complications, their blood white blood cells were almost gone, and their bone marrow was scorched. , exhausted.
Alexander’s conjecture: Mustard gas, with its enormously toxic effects on white blood cells and inhibition of cell division, may be used to treat certain cancers.
(A soldier inspecting a mustard gas warhead. Credit: Bateman Archives)
Previously, in 1942, Goodman et al. of Yale University had injected nitrogen mustard (a semi-finished product of mustard gas, a nitrogen-containing analog) into mice with lymphoma, and the lumps became dramatic. Shrinking, a phenomenon never seen before, and multiple repetitions worked. To do this, they injected a small dose of nitrogen mustard into a 48-year-old silversmith with lymphoma with the consent of the patient and his doctor. The patient’s glands filled with sick white blood cells miraculously shrunk after the nitrogen mustard treatment, without the toxic side effects of mustard gas. The patient was in remission and survived for 6 months [2].
Alexander’s top-secret report and Yale clinical trials caught the attention of his boss, Cornelius P. Rhodes. Rhodes also has an identity, he is the director of New York Memorial Hospital, engaged in cancer treatment research. Rhodes believed nitrogen mustard could be used to treat cancer in tiny doses.
In 1945, Rhodes persuaded auto tycoons Alfred P. Sloan and Charles F. Kettering to invest in the establishment of the Sloan Kettering Cancer Institute to study large-scale synthesis Nitrogen mustard technology and conduct clinical trials. In 1949, nitrogen mustard became the first experimental chemotherapy drug approved by the U.S. Food and Drug Administration (FDA) and was successfully used to treat non-Hodgkin lymphoma [1].
In this way, the “King of Poison Gas” mustard gas turned into the world’s first chemotherapeutic drug, nitrogen mustard.
Nowadays, nitrogen mustards have derived many new drugs, the most representative and most commonly used is cyclophosphamide, which is clinically used for the treatment of acute or chronic lymphocytic leukemia, malignant lymphoma , Multiple myeloma has better curative effect.
If nitrogen mustard is “a blessing in disguise” that opened the era of chemotherapy, then the discovery of paclitaxel is a typical example of “finding a needle in a haystack” for the development of anticancer drugs.
After World War II, the National Cancer Institute conducted a large-scale screening of anti-cancer drugs, hoping to screen anti-cancer drugs from natural extracts of animals and plants. In the following 20 years, researchers collected and tested more than 30,000 samples, and found one of the best natural anti-cancer drugs – paclitaxel!
(Yew, an endangered plant in China.)
The story goes back to the summer of 1962. The team of American botanist Arthur Barclay encountered a 7-meter plant in Gifford Pinchot National Forest in Washington State. The tall Pacific yew (also known as Taxus brevifolia in China), Buck sent samples of its bark, branches and fruit to the National Cancer Institute. Little do they know, the humble yew bark has since rewritten the history of the world’s anticancer drugs.
These raw materials were passed to two chemists, Wall and Varney, who obtained a crude extract from the bark. Experiments have found that this crude extract has a strong inhibitory effect on the growth of leukemia, Kaposi’s sarcoma, melanoma and other tumor cells cultured in vitro. In September 1966, Wall and Varney purified 0.5 g of the active ingredient from 12 kg of yew bark. Because it was obtained from yew trees, they called the substance paclitaxel.
In May 1971, Wall and Varney introduced paclitaxel, a natural compound with initial antitumor activity, to the world through the Journal of the American Chemical Society. But trouble is coming. To develop paclitaxel into a drug, it is necessary to carry out animal experiments, toxicological experiments and subsequent clinical trials of paclitaxel, which all require a large amount of paclitaxel.
However, yew grows very slowly and is not easy to reproduce. A 100-year-old yew can only get about 2 kg of bark.
Wall used 21 kilograms of yew bark when he first discovered the activity of paclitaxel. By the end of 1966, the demand for yew bark had reached 170 kg. In 1980, when paclitaxel entered the stage of animal experiments, the demand for yew bark reached an astonishing 10 tons. Because of the scarcity of raw materials, the National Cancer Institute did not accumulate about 3 kilograms of paclitaxel until 1989.
In 1988, the National Cancer Institute of the United States announced the first phase II clinical results, paclitaxel was very effective in treating melanoma, and the effective rate in recurrent ovarian cancer was as high as 30%. The result caused a global sensation because at the time there were no drugs available for tumor recurrence. As a result, paclitaxel became a star drug and was soon approved for marketing in December 1992.
Due to the serious damage to forest resources caused by the large-scale extraction of paclitaxel, the United States has legal protection of yew, and the source of the drug has turned to developing countries. At that time, China’s lag in the recognition of the value of yew and its legislation made yew unfortunate to become a victim of the paclitaxel boom. Chinese yew and Pacific yew are the same species. According to a survey conducted by the forestry department in 1996, there were 3.54 million yew trees in Yunnan province, accounting for 55% of the national total [3].
(In July 2013, the Meishan Forest Police seized the illegally felled yew. Picture Yuanmeishan Forest Public Security)
Since 1992, the yew bark war has started in the northwestern part of Yunnan Province, and a large number of businessmen have flocked to the forest area to purchase yew bark, resulting in millions of yew trees being peeled. die. Only a company in Yunnan Hande purchased 5,519.312 kilograms of yew bark and 10,765.475 grams of semi-finished products, and produced and exported about 140 kilograms of semi-finished and finished taxol, equivalent to at least 1,400 tons of yew bark. [3] In just a few years, the yew resources in Yunnan, Jiangxi, and Northeast China have been destroyed, and the yew has been cut down into a rare and endangered plant at the national level. Almost all paclitaxel produced in China is exported to the United States.
Until 2003, the national legislation banned the export of paclitaxel and semi-finished products, and a number of major cases such as Yunnan Hande were sentenced successively. In addition, French and American scientists successively discovered semi-synthetic paclitaxel methods. The wind of yew peeling gradually subsided.
Targeted drugs are characterized by precise strikes. It is like a “missile” that can precisely destroy tumor cells in the body, which is much more effective than the indiscriminate bombardment of conventional chemotherapy, and has far fewer side effects. There are two typical representative drugs: small molecule targeted drugs imatinib, gefitinib, anlotinib, crizotinib, etc., macromolecule targeted drugs rituximab, trastuzumab, etc. Monoclonal antibody, bevacizumab, etc.
With the rise of genomics, since the 1980s, scientists have successively discovered that there are many variant genes and unique antigens in tumor cells, and found some clear and specific antigens from hundreds of millions of gene fragments. to try to develop specific drugs to inhibit cancer.
In 2001, the first small-molecule targeted drug, imatinib, was born, ushering in the era of targeted drug therapy.
Most importantly, the success of imatinib has opened up a new avenue for the development of later “tinib” drugs, where scientists can precisely simulate the structure of the compound to bind to the target. The invention of new anticancer drugs completely subverts the traditional “needle in a haystack” of drug research and development.
In the 1980s, scientists discovered that there was an interlaced translocation between chromosome 9 and chromosome 22 in patients with chronic myeloid leukemia. The bcr gene on the chromosome is fused, resulting in a bcr/abl fusion gene. This mutant gene synthesizes a special tyrosine kinase, which continuously interferes with molecular signal transduction in cells. The continuous proliferation and apoptosis of leukemia cells are out of control, resulting in the occurrence of chronic myeloid leukemia.
(The misplaced chromosomes 9 and 22 in a leukemia patient. Source: drugood)
Maybe many people are relatively unfamiliar with kinases. There are 518 kinase-encoding genes in the human genome, encoding 518 kinases. These kinases can phosphorylate human proteins, and if the kinases are abnormally activated (mutation, overexpression, fusion expression, etc.), it will cause tumors, inflammation and other diseases.
For conventional kinases, their active expression is tightly controlled and will not suddenly run out of control; but the tyrosine kinase expressed by bcr/abl is different, it is not controlled and always Being active, it constantly sends the wrong signals to cells, causing cells to divide uncontrollably, eventually causing cancer.
After the discovery of the pathogenic mechanism of leukemia, scientists launched a series of projects to find protein kinase inhibitors. This is very difficult, because there are 518 kinases in the human body, and most of them are of similar types. It can be said that it is extremely difficult to inhibit only a certain kinase through a drug.
Fortunately, researchers discovered a derivative of 2-phenylaminopyrimidine that exhibits druggable potential, inhibiting both serine/threonine kinases and tyrosine kinases. However, this derivative is less specific and cannot be used directly for treatment, but it provides a light for new drug development.
At this time, the “five tiger generals” in the development of imatinib appeared.
(Brian Drucker and patients participating in the trial. Source: drugood )
The first “Five Tigers” to appear was Brian Drucker of the Oregon Health Sciences University Cancer Institute, who discovered that different kinases have different ATP-binding pocket states. Simply put, the containers used to synthesize kinases are different, just like we use cups for drinking water, bowls for soup, and plates for vegetables. Finding differences in kinases can hopefully lead to targeted drug development.
The second “Five Tiger Generals” to appear is a big moneymaker, Alex Matt, then the owner of the Kiba Cargill Company. He believed that Drucker’s theory was correct, but at that time kinase research was a small market and was completely unprofitable. He defied all opposition and supported Drucker’s research. At the same time, he brought in three other “five tiger generals” for the development of imatinib: Nick Leiden, who is responsible for synthesizing small molecule drug structures, and four of the “five tiger generals”. Merman, Elizabeth Bagden, who was in charge of the initial screening experiments for the drug.
In the lab, they work day and night to synthesize hundreds of small molecular structures, sometimes adding or removing a group, or removing or adding an atom, based on the new compound. The activity determines how to continue to remodel the molecule, and a new cycle starts again, and so on.
The process of optimizing drug structures and testing drug efficacy experiments is very tedious and lengthy, like formulating hundreds of keys and then trying keyholes one by one.
Finally in 1992, Zimmerman discovered in an experiment that the inhibitor numbered STI751 showed extremely high specific inhibitory ability. It can successfully inhibit the tyrosine kinase of leukemia cells without affecting the metabolism of normal cells [4].
The story does not end here. Since the number of patients with chronic myeloid leukemia is very small, there are only 1 or 2 patients in about 100,000 people, so clinical trials are very difficult and can only be carried out in individual cases. between patients.
At this time, a great leukemia patient appeared. Her name was Susan McLamara. After hearing the news of the STI751 clinical trial from her patients, she launched an initiative around the world to call on Everyone come to participate in the test, don’t be afraid of death! And collected the signatures of more than 4,000 patients, and wrote a letter to the pharmaceutical company requesting expansion of production.
Not only that, but she bravely asked the doctor to test the highest dose of the drug on her. You know, in toxicology experiments, STI751 at a dose of 600mg can cause liver failure in dogs. But she firmly said that if my death can bring life to other patients, then my death is worthwhile!
(a leukemia patient participating in the trial in front of her tombstone, source: drugood)
In 1999, STI751, which lived up to expectations, entered the Phase II clinical trial. After one and a half years of treatment, the progression-free survival rate of patients was as high as 89.2%. Less than 3 months after the results of the phase II clinical study were announced, the US FDA quickly approved the launch of this drug, which is imatinib, which pioneered the era of targeted therapy.
After reading these 3 stories, I believe everyone knows how difficult it is to develop an anticancer drug.
Scientists need to screen layer by layer from natural compounds (plants, minerals, fungi, etc.) or small molecule compound libraries, purify and experiment step by step in thousands of raw materials, and continuously To optimize the molecular structure of the drug, increase the efficacy and reduce the toxic and side effects. I am also grateful to the persistence of so many scientists in the world and the dedication of so many patients that the current anti-cancer drugs have been developed, and tumor patients have a weapon against death.
Let’s pay our respects to these great “drug hunters” and “drug men”!
Reviewer:
Yibo Wu| Master of Clinical Pharmacy, School of Pharmacy, Peking University
Li Xin D| Master of Clinical Pharmacy, School of Pharmacy, Peking University
References
[1]How a WWII Disaster—and Cover-up—Led to a Cancer Treatment Breakthrough.https:https://www.history.com/news/wwii-disaster-bari- mustard-gas
[2]Siddhartha Mukherjee. The King of Diseases: A Cancer Passage
[3] Yew. CCTV “News Investigation”. http:https://www.cctv.com/zhuanti/newsprobe/dangan/4977_3.html
[4]STI-571: an anticancer protein-tyrosine kinase inhibitor.https:https://pubmed.ncbi.nlm.nih.gov/13679030/
*The content of this article is for the popularization of health knowledge and cannot be used as a specific diagnosis and treatment suggestion, nor can it replace the face-to-face consultation of a licensed physician, and is for reference only.
*The copyright of this article belongs to Tencent Medical Dictionary. Unauthorized reprinting by media is prohibited. Illegal reprinting will be investigated for legal responsibility according to law. Individuals are welcome to forward to the circle of friends.