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    Home > Medical News > Medical World News > What fortresses need to be conquered in the treatment of leukemia after the advent of Gleevec

    What fortresses need to be conquered in the treatment of leukemia after the advent of Gleevec

    • Last Update: 2020-02-17
    • Source: Internet
    • Author: User
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    I believe many people still remember the movie "I am not the God of medicine" released in the previous two years This domestic comedy blockbuster won the praise of many audiences with the plot of "seeking medical treatment" with tears in the laughter, and also let us glimpse the hardships and helplessness of a leukemia patient in the process of fighting the disease There are many types of leukemia The main character suffers from chronic myeloid leukemia (CML), which accounts for 70% of China's chronic leukemia In western countries, the proportion of CML in chronic leukemia is relatively low, but it also reaches 30% left and right Photo source: CDC, USA Leukaemia was first identified as a unique disease in the early 19th century, and the early related descriptions are highly consistent with some characteristics of CML CML is generally divided into three stages: chronic stage, accelerated stage and cataclysmic stage The course of CML can last for several years, but it often dies within half a year in the cataclysmic stage For a long time, CML has been regarded as a terminal disease It was not until the birth of the "magic drug" Lenin, which represents the hope of life in the film, which is actually called Gleevec (imatinib), that a major breakthrough was made in the treatment of this disease Since it was approved in 2001, Gleevec has made remarkable achievements in the treatment of chronic leukemia, which can be called a miracle of anti-cancer that is hard to replicate So, after nearly 20 years, what is the progress in the field of CML treatment? In the face of this once incurable disease, are we "once and for all"? In 1956, a young man named Peter Nowell retired from the Navy and returned to his hometown of Philadelphia There, he joined the Department of pathology at the University of Pennsylvania, where he studied leukemia and lymphoma In order to find out the relationship between chromosomes and blood cancer, he decided to use a new staining technology to mark chromosomes, so as to see their structure more clearly - cells grow to a certain stage on glass chips, and then are bubbled in water and split Subsequently, the Giemsa staining, which infiltrates the cell, enables the chromosomes to emerge from the cell His new attempt brought with it the harvest Before long, he and his graduate students found an interesting phenomenon: in cancer cells of CML patients, chromosome 22 is significantly shorter ▲ chromosome 22 of some leukemia patients should be significantly shorter (photo source: nature) The researchers are acutely aware that this chromosomal abnormality may be the underlying cause of this type of chronic leukemia In a follow-up study, the researchers looked at the chromosomes of seven leukemia patients, each with a short chromosome 22 Over the next few years, Novell and his colleagues published a number of papers announcing their findings to the world That means two things First of all, this genetic variation is essential for this type of cancer attack; second, these tumors do grow from the individual cells that have mutated The whole field of cancer research is shaking! In recognition of this important finding made by the University of Pennsylvania, the abnormal chromosome 22 in patients was also named "Philadelphia chromosome" The discovery of Philadelphia chromosome is the first important contribution to the biological basis of CML The discovery of Philadelphia chromosome is an important breakthrough, but not an end point We still don't know the pathogenicity behind the chromosomal abnormality In 1973, the team of Professor Janet Rowley of the University of Chicago found that the Philadelphia chromosome was short because of the translocation of chromosome - part of the exchange between human chromosome 9 and 22, which made chromosome 22 short She is keen to point out that behind this particular translocation, there must be some special carcinogenic mechanism ▲ the formation mechanism of Philadelphia chromosome (photo source: by aryn89 [CC by-sa 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons) It took another 10 years to understand the carcinogenic mechanism In 1983, researchers from the National Cancer Institute (NCI) and Erasmus University found that due to the cross translocation between the two chromosomes, the abl gene on chromosome 9 happened to be connected with the BCR gene on chromosome 22, resulting in a BCR abl fusion gene This fusion gene encodes a unique tyrosine kinase For the conventional tyrosine kinases, their activity is strictly controlled and not out of control suddenly, but BCR ABL protein is different It is not controlled by other molecules and has been active It's like the cell locks the gas pedal, causing uncontrolled cell division and causing cancer In 1990, BCR ABL was proved to be able to induce CML in a mouse model, thus proving its central role in the pathogenesis of the disease At this time, 30 years have passed since the discovery of Philadelphia chromosome Although the pathogenesis of CML was not clear until the 1990s, the exploration of its treatment has already begun In the 19th century, researchers discovered the efficacy of arsenic in the treatment of CML In the early 1980s, interferon α came out, and radiotherapy, followed by alkylating agents and hydroxyurea became the main means of treatment In the 1980s, although there was a risk of death, allogeneic stem cell transplantation could bring long-term disease-free survival or cure certain patients However, these traditional treatment methods, for the vast majority of CML patients, are still only a slim hope It is urgent to find more effective treatment With the development of the pathogenesis of CML, it is believed that BCR - ABL protein kinase inhibitors can target CML In the late 1980s, scientists from Ciba geigy (now owned by Novartis) launched a series of projects to find protein kinase inhibitors In a project for protein kinase C (PKC), they found that a derivative of 2-phenylaminopyrimidine showed the potential of the drug, which can inhibit serine / threonine kinase and tyrosine kinase at the same time Although the derivative has poor specificity and can not be directly used for treatment, it provides a starting point for new drug developers On the basis of this compound, researchers have made a series of synthesis attempts, not only to optimize the characteristics of this molecule, but also to make oral medication possible ▲ molecular structure formula of Gleevec (photo source: fuse809 [public domain]) After a series of design and modification, this molecule shows a very high specific inhibition ability As long as cells express BCR ABL protein, their growth will be inhibited by this molecule Researchers believe it's time to move it to the next stage In mouse experiments, the researchers further optimized the course and dose of the molecule, and obtained positive data In June 1998, the BCR ABL inhibitor named imatinib ushered in a historic day - it finally entered the human trial stage In this phase 1 clinical trial, the main purpose of the researchers is to find the maximum tolerable dose and explore the safety of the drug The study recruited a group of patients who had been treated but were still in a serious condition to receive daily oral imatinib therapy Studies have shown that the drug is not only well tolerated, but also miraculously effective: 53 of the 54 patients who received 300 mg of the drug developed complete remission (CHr) in hematology This gratifying result quickly brought imatinib to phase 2 clinical trial The second phase of clinical trial, which was launched in 1999, once again verified the positive effect observed in the first phase What's more gratifying is that these effects seem to be quite lasting: after one and a half years of treatment, the progression free survival rate of patients still reaches 89.2% Based on its excellent therapeutic effect, the US FDA accelerated the approval of the new drug for chronic myeloid leukemia after phase II clinical trial The product name of this drug is known as Gleevec After being approved, the researchers completed three phases of clinical trials Compared with standard therapy, it shows significant effect on all indexes Before the birth of Gleevec, only 30% of patients with chronic myeloid leukemia could live for 5 years after diagnosis Gleevec raised the number from 30% to 89%, and five years later, 98% of patients still had complete hematologic remission To this end, it has also been included in the World Health Organization's standard list of essential drugs Gleevec is the first molecular targeted drug for anti-cancer Since it was approved in 2001, it has made remarkable achievements in the treatment of chronic leukemia, which can be regarded as a miracle of anti-cancer However, although most patients, especially those in chronic phase, can be relieved by Gleevec, several BCR ABL related or unrelated drug resistance mechanisms appear after it becomes the first-line treatment of CML, and about 4% of patients have drug resistance to it every year People's pursuit of a complete cure for chronic myeloid leukemia has not slowed down After the mechanism of action of Gleevec was elucidated, people continued to develop new specific drugs to overcome drug resistance, which led to the second and third generation of tyrosine kinase inhibitors (TKIs) In June 2006, dasatinib of Bristol Myers Squibb was approved by FDA It is an oral multi kinase inhibitor for adults with CML at all stages of disease who are resistant or intolerable to treatment regimens including Gleevec The gene research of the patients with resistance to Gleevec showed that the kinase domain of BCR - ABL protein in these patients had mutation, which interfered with the binding of Gleevec and kinase The binding of dasatinib and ABL protein is not strict to the conformation, and it still has the activity to other Gleevec resistant mutant cells except T315I mutant In fact, dasatinib can inhibit the proliferation of BCR ABL positive bone marrow precursor cells from patients with sensitive or resistant to Gleevec and prolong the survival time of patients with resistant to Gleevec Source: dasatinib, fvasconcellos [public domain]; nilotinib, bosudinib, ponatinib, fuse809 [public domain] Nilotinib of Novartis was first approved by FDA in October 2007 to treat CML patients with resistance or intolerance to existing therapies Like dasatinib, this compound has multiple inhibitory activities, which can inhibit many members of ABL and Src kinase family Bosutinib of Pfizer was first approved in the United States in September 2012 for the treatment of Philadelphia chromosome positive CML (Ph + CML) adult patients with chronic, accelerated or cataclysmic stage who are resistant or intolerant to previous therapies A randomized, multicenter, multinational, open label phase 3 clinical study showed that patients receiving bosudinib achieved a higher proportion of major molecular remission (MMR) after 12 months compared with the active control group receiving standard therapy, while the complete cytogenetic remission rate (ccyr) of bosudinib was 77.2% and 66.4% in the control group Panatinib is the third generation TKI developed by ariad, which was approved by the US FDA in December 2012 for the treatment of tyrosine kinase inhibitor resistance or
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