The twists and turns of the development of the first targeted antitumor drug

In 2018, China released "I'm Not the God of Medicine", which tells the story of a pharmacy owner who made a fortune by smuggling Indian generic drugs for leukemia treatment and finally could not escape the law. But what the film really focuses on is the problem that ordinary people can't afford to see a doctor. At the same time, the first targeted anti-tumor drug, imatinib, that no one knows about except leukemia patients, is also introduced.

In order to find the carcinogenic mechanism, in 1983, the National Cancer Institute of the United States found that due to the staggered translocation between the two chromosomes, a gene on chromosome 9 happened to be linked to a gene on chromosome 22. The fusion gene encodes a peculiar tyrosine kinase (target of antineoplastic drugs) that is not controlled by other molecules and is always active. It's as if the cells are locking the gas pedal of the car (can't brake), causing the cells to divide uncontrollably, causing cancer.

Targeted therapy opens up new directions for cancer chemotherapy

The so-called tumor molecular targeted therapy is to use the specific (or relatively specific) structural molecules of tumor tissues or cells as targets, and use antibody ligands that specifically bind to these molecules to achieve direct or targeted therapy. Class therapy is like shooting a target. There is a target in front of the gun to shoot, in order to hit the target accurately. To make a simple analogy, the specific structure on tumor cells is like a keyhole, and the targeted drug is like a one-to-one matching key. Once the two are successfully paired, the apoptosis of tumor cells can be started. Compared with traditional chemotherapy drugs, molecular targeted drugs act on specific protein molecules, enzymes, and nucleotide fragments, with strong selection specificity, obvious therapeutic effects, and fewer adverse reactions; while traditional antitumor drugs act on cells, deoxyribose Nucleic acid (DNA), ribonucleic acid (RNA) or protein, with poor selectivity and large differences in efficacy, often have serious adverse reactions in the digestive tract and blood system, such as vomiting, hair loss, bone marrow suppression, anemia, and decreased white blood cell or red blood cell count.

The international common name of imatinib is imatinib mesylate, which is a protein tyrosine kinase inhibitor. In fighting tumors, protein tyrosine kinases are very important. This enzyme is a kind of protein with tyrosine kinase activity, which is divided into receptor type and non-receptor type. Protein tyrosine kinases play an important role in intracellular signal transduction pathways, regulating a series of physiological and biochemical processes such as cell growth, differentiation, and death in vivo. The imbalance or disorder of protein tyrosine kinase function will lead to a series of diseases in the human body. More than 50% of proto-oncogenes and oncogene products have protein tyrosine kinase activity, and their abnormal expression will lead to the regulation of cell proliferation. disorders, which in turn lead to tumorigenesis. In addition, abnormal expression of tyrosine kinases is also closely related to tumor invasion and metastasis, tumor angiogenesis, and tumor chemotherapy resistance. Therefore, targeting protein tyrosine kinases to seek new drugs has become a hot spot in the international anti-tumor drug research.

The development of the first targeted anti-tumor drug imatinib is indeed "twisted and twisted"

Imatinib is used to treat chronic myeloid leukemia and gastrointestinal stromal cell tumor, but its birth has been twists and turns. In the 1950s, when scientists used advanced colchicine solution chromosome preparation, an abnormal chromosome was found in patients with chronic myeloid leukemia (CML). It was named Philadelphia chromosome because it was first discovered in Philadelphia. become a hallmark of leukemia. Since then, genetic defects and cancer formation have begun. After more than 30 years of research and continuous efforts, the molecular biology pathogenesis of chronic myeloid leukemia was finally understood. Simply put, the Philadelphia chromosome expresses a fusion protein called "Bcr-Abl" (a gene with high tyrosine kinase activity), which is an activated form of a tyrosine kinase that continuously sends The signal, which leads to a massive increase in human leukocytes (infinite proliferation), becomes the pathogenesis of leukemia. Since this mutant protein can cause unlimited proliferation of white blood cells, it also means that a drug can be used to block this pathway, which is the premise of the birth of imatinib.

In the late 1980s, scientists launched a series of projects to find protein kinase inhibitors. After a series of designs, finally found a resounding drug name - imatinib. In June 1998, in a phase 1 clinical trial, the study enrolled a group of patients with severe leukemia who had been treated, and received daily oral imatinib. The study showed not only well tolerated but also miraculous efficacy, with 53 of 54 patients receiving the 300 mg dose experiencing complete hematologic remission (near recovery).

The Phase 2 clinical trial initiated in 1999 reconfirmed the significant efficacy observed in the Phase 1 trial. Even more gratifying is that these effects appear to be quite durable, with a progression-free survival rate of 89.2% after 1.5 years of treatment. The results of post-marketing clinical trials showed that imatinib showed significant efficacy in all indicators. Before the advent of imatinib, only 30% of chronic myeloid leukemia patients lived more than five years after diagnosis. But the new drug raised that figure from 30% to 89%, and after five years, 98% of patients were still in complete hematologic remission.

In 1996, American hematology experts and French biologists published papers, which caused a sensation in the world and were known as "silver bullets". In a study that included 31 patients with Philadelphia chromosome-positive chronic myeloid leukemia, all patients had complete hematologic remission, and one-third had concurrent complete cytogenetic remission. In 2001, the U.S. FDA approved imatinib at a record-breaking speed (approval process was less than 3 months) for the treatment of Philadelphia chromosome-positive, chronic myeloid leukemia patients with interferon treatment ineffective treatment of acute exacerbation, accelerated and chronic phases . In a phase 2 clinical study involving 1027 patients jointly conducted by 6 countries, 454 patients with chronic myeloid leukemia in chronic phase who failed interferon received oral imatinib, and 415 patients (95%) achieved complete hematological response, and 415 patients (95%) achieved complete blood efficacy. 248 patients (60%) had primary cytogenetic response; 181 accelerated and 229 acute disease patients had complete hematologic response in 34% and 7%, respectively, and primary cytogenetic response was unexpectedly 34%, respectively and 16%.

A movie that changed the fate of critically ill patients such as tumors and leukemia. In 2017, the Chinese government reduced or exempted tariffs on anti-tumor drugs, increased the evaluation of the consistency between original research drugs and generic drugs, lowered the prices of the varieties that entered the National Medical Insurance Catalogue through negotiations, and increased the number of medical and health services (drugs, consumables) anti-corruption efforts and increased regulation of drug prices. The Ministry of Human Resources and Social Security of the People's Republic of China included 36 negotiated drugs in the "National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug Catalog (2017 Edition)", of which 15 are tumor treatment drugs, including trastuzumab, rituximab , bortezomib and other targeted anti-tumor drugs with significant efficacy and high price.

In 2018, the state included targeted anti-tumor drugs and anti-leukemia drugs into the National Essential Medicines List (2018 Edition) and the Medical Insurance Insurance Drug List (2019 Edition), including imatinib tablets and capsules. In addition, the "Drug Registration Law" has also been revised. Imported medicines brought from overseas in the past, without registration, are counted as "fake medicines" and will face penalties (just like the owners of health pharmacies), but after the revision, they can be brought with them for a sufficient course of treatment. doses of imported medicines. The price of these drugs has been greatly reduced, and the increase in the payment of medical insurance has reduced the cost of patients. Therefore, I believe that our drug prices will become more and more