Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
) among others, is an oral
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
medication used to treat
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.
[ Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kinases such as ]CSF1R
Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). CS ...
, ABL, c-KIT
Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding dif ...
, FLT3
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the ''FLT3'' gene. FLT3 is a cyto ...
, and PDGFR-β
Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the ''PDGFRB'' gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies.
Gene
The ''PDGFRB'' gene is located on hu ...
. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...
(ALL) that are Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
-positive (Ph+), certain types of gastrointestinal stromal tumor
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior ...
s (GIST), hypereosinophilic syndrome
Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count (≥ 1500 eosinophils/mm³) in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous sys ...
(HES), chronic eosinophilic leukemia
Chronic eosinophilic leukemia is a form of cancer in which too many eosinophils are found in the bone marrow, blood, and other tissues. Most cases are associated with fusion genes.
Signs and symptoms
Signs and symptoms may include weight loss, f ...
(CEL), systemic mastocytosis
Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors.
People affected by masto ...
, and myelodysplastic syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
.[
Common side effects include vomiting, diarrhea, muscle pain, headache, and rash.][ Severe side effects may include fluid retention, ]gastrointestinal bleeding
Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may include ...
, bone marrow suppression
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity ( leukocytes), carrying oxygen ( erythrocytes), and/or those responsible for normal blood clotting ...
, liver problems
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the s ...
, and heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
.[ Use during ]pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
may result in harm to the baby.[ Imatinib works by stopping the Bcr-Abl tyrosine-kinase.][ This can slow growth or result in ]programmed cell death
Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...
of certain types of cancer cells.[
Imatinib was approved for medical use in the United States in 2001.][ It is on the ]World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. A generic version became available in the UK as of 2017.
Medical uses
Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumor
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior ...
s (GISTs) and a number of other malignancies
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
. In 2006 the FDA expanded approved use to include dermatofibrosarcoma protuberans
Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive malignant cutaneous soft-tissue sarcoma. DFSP develops in the connective tissue cells in the middle layer of the skin (dermis). Estimates of the overall occurrence of DFSP in the ...
(DFSP), myelodysplastic
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
/myeloproliferative diseases (MDS/MPD), and aggressive systemic mastocytosis
Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors.
People affected by mas ...
(ASM).
Chronic myelogenous leukemia
The U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) has approved imatinib as first-line treatment for Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
-positive CML, both in adults and children. The drug is approved in multiple contexts of Philadelphia chromosome-positive CML, including after stem cell transplant, in blast crisis, and newly diagnosed.
Due in part to the development of imatinib and related drugs, the five-year survival rate for people with chronic myeloid leukemia increased from 31% in 1993, to 59% in 2009, to 70% in 2016. Starting from 2011, it became clear that CML patients who continue to respond to imatinib have the same or almost the same life expectancy as the general population.
Gastrointestinal stromal tumors
The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence. The drug is also approved in unresectable KIT-positive GISTs.
Dermatofibrosarcoma protuberans (DFSP)
The FDA granted approval for the treatment of dermatofibrosarcoma protuberans
Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive malignant cutaneous soft-tissue sarcoma. DFSP develops in the connective tissue cells in the middle layer of the skin (dermis). Estimates of the overall occurrence of DFSP in the ...
(DFSP) patients in 2006. Specifically adult patients with unresectable, recurrent and/or metastatic
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
dermatofibrosarcoma protuberans (DFSP). Prior to approval DFSP was considered unresponsive to chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
treatments.
Other
The FDA has approved imatinib for use in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
/myeloproliferative
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid gr ...
diseases associated with platelet-derived growth factor receptor
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellu ...
gene rearrangements, aggressive systemic mastocytosis
Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors.
People affected by mas ...
without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome
Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count (≥ 1500 eosinophils/mm³) in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous sys ...
and/or chronic eosinophilic leukemia
Chronic eosinophilic leukemia is a form of cancer in which too many eosinophils are found in the bone marrow, blood, and other tissues. Most cases are associated with fusion genes.
Signs and symptoms
Signs and symptoms may include weight loss, f ...
who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.
For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.[
*] According to a small trial, imatinib is an effective drug in some patients with aggressive fibromatosis
Aggressive fibromatosis or desmoid tumor is a rare condition. Desmoid tumors arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wou ...
.
Contraindications and cautions
The only known contraindication to imatinib is hypersensitivity to imatinib. Cautions include:
* Hepatic impairment
* Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities
* Pregnancy, risk of embryo-fetal toxicity
* Risk of fluid retention
* Risk of growth stunting in children or adolescents
Side effects
The most common side effects include nausea, vomiting, diarrhea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite; weight gain, reduced number of blood cells ( neutropenia, thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
, anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
), and edema.
Although rare, restoration of hair color has been reported as well.
Severe congestive cardiac failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, an ...
is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.
If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
.
Overdose
Medical experience with imatinib overdose is limited. Treatment is supportive.[ Imatinib is highly plasma protein-bound:][ dialysis is unlikely to be helpful removing imatinib.
]
Interactions
Its use is advised against in people on strong CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
inhibitors such as clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
, chloramphenicol, ketoconazole, ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...
and nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...
due to its reliance on CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
for metabolism.[ Likewise it is a ]CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
, CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2D ...
and CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs.[ Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of ]itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mo ...
, clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
, grapefruit juice
Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.The World's Healthiest Foods; Grapefruit. ''The ...
, among others. Conversely, CYP3A4 inductors like rifampicin and St John's Wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...
reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin
Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of hear ...
, ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...
, pimozide
Pimozide (sold under the brand name Orap) is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis ...
, warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
, metoprolol
Metoprolol, sold under the brand name Lopressor, among others, is a selective β1 receptor blocker medication. It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an a ...
, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.
As with other immunosuppressants, application of live vaccine
An attenuated vaccine (or a live attenuated vaccine, LAV) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less ...
s is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid
A toxoid is an inactivated toxin (usually an exotoxin) whose toxicity has been suppressed either by chemical (formalin) or heat treatment, while other properties, typically immunogenicity, are maintained. Toxins are secreted by bacteria, whereas ...
vaccines do not hold this risk, but may not be effective under imatinib therapy.
Pharmacology
Mechanism of action
Imatinib is a 2-phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
amino
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the ''TK'' active site, leading to a decrease in activity.
There are a large number of ''TK'' enzymes in the body, including the insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose ho ...
. Imatinib is specific for the ''TK'' domain in '' abl'' (the Abelson proto-oncogene), c-kit
Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding dif ...
and PDGF-R
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cell ...
(platelet-derived growth factor
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
leads to a fusion protein of ''abl'' with ''bcr'' (''breakpoint cluster region''), termed ''bcr-abl''. As this is now a constitutively active tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
, imatinib is used to decrease ''bcr-abl'' activity.
The active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
s of tyrosine kinases each have a binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
for ATP. The enzymatic activity catalyzed
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
by a tyrosine kinase is the transfer of the terminal phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phospho ...
from ATP to tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
residues on its substrates, a process known as protein tyrosine phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
. Imatinib works by binding close to the ATP binding site of ''bcr-abl'', locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.
Imatinib is quite selective for ''bcr-abl'', though it does also inhibit other targets mentioned above (c-kit and PDGF-R), as well as ABL2 (ARG) and DDR1 tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
s and NQO2 – an oxidoreductase. Imatinib also inhibits the ''abl'' protein of non-cancer cells, but these cells normally have additional redundant tyrosine kinases, which allows them to continue to function even if ''abl'' tyrosine kinase is inhibited. Some tumor cells
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
, however, have a dependence on ''bcr-abl''. Inhibition of the ''bcr-abl'' tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti- apoptopic functions, leading to tumor cell death.
Other pathways affected
The Bcr-Abl pathway has many downstream pathways including
* the Ras/MapK pathway
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling m ...
, which leads to increased proliferation due to increased growth factor-independent cell growth.
* It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion.
* The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2
Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...
is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival.
* The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.
Pharmacokinetics
Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
and is mediated by several isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
s of the cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
system, including CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
and, to a lesser extent, CYP1A2
Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene.
Function
...
, CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2D ...
, CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
, and CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...
. The main metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
, ''N''-demethylated piperazine
Piperazine () is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste.
The piperazines are a broad ...
derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites; only 25% is eliminated unchanged. The half-lives
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
of imatinib and its main metabolite are 18 h and 40 h, respectively. It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome
Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count (≥ 1500 eosinophils/mm³) in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous sys ...
, and dermatofibrosarcoma protuberans
Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive malignant cutaneous soft-tissue sarcoma. DFSP develops in the connective tissue cells in the middle layer of the skin (dermis). Estimates of the overall occurrence of DFSP in the ...
.
Chemistry
Synthesis
History
Imatinib was invented in the late 1990s by scientists at Ciba-Geigy
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loca ...
(which merged with Sandoz
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loca ...
in 1996 to become Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
), in a team led by the British biochemist Nicholas Lydon
Nicholas B. Lydon FRS (born 27 February 1957) is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL ...
and that included Elisabeth Buchdunger and Jürg Zimmermann, and its use to treat CML was driven by oncologist Brian Druker
Brian J. Druker (born April 30, 1955) is a physician-scientist at Oregon Health & Science University, in Portland, Oregon. He is the director of OHSU's Knight Cancer Institute, Jeld-Wen Chair of Leukemia Research, and professor of medicine. In 2 ...
of Oregon Health & Science University
Oregon Health & Science University (OHSU) is a
public research university focusing primarily on health sciences with a main campus, including two hospitals, in Portland, Oregon. The institution was founded in 1887 as the University of Oregon Med ...
(OHSU). Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini
Carlo Gambacorti-Passerini (born 26 August 1957) is an Italian oncology, oncologist and hematologist known for his contributions to cancer (disease), cancer research.
He is Professor of Internal Medicine and Hematology at the University of Milan ...
, a physician, scientist, and hematologist at the University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital
Hammersmith Hospital, formerly the Military Orthopaedic Hospital, and later the Special Surgical Hospital, is a major teaching hospital in White City, West London. It is part of Imperial College Healthcare NHS Trust in the London Borough of ...
in London, and later on by Charles Sawyers
Charles L. Sawyers (born 1959) is a Howard Hughes Medical Institute (HHMI) investigator who holds the Marie-Josée and Henry R. Kravis Chair of the Human Oncology and Pathogenesis Program (HOPP) at Memorial Sloan Kettering Cancer Center (MSK) ...
of Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center (MSK or MSKCC) is a cancer treatment and research institution in the borough of Manhattan in New York City, founded in 1884 as the New York Cancer Hospital. MSKCC is one of 52 National Cancer Institute– ...
in New York.
Imatinib was developed by rational drug design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activa ...
. After the Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
mutation and hyperactive ''bcr-abl'' protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening
High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling ...
, they identified 2-phenylaminopyrimidine. This lead compound
A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacology, pharmacological or biological activity likely to be therapeutical ...
was then tested and modified by the introduction of methyl and benzamide
Benzamide is a organic compound with the chemical formula of C6H5C(O)NH2. It is the simplest amide derivative of benzoic acid
Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benz ...
groups to give it enhanced binding properties, resulting in imatinib.
When Novartis tested imatinib in rats, mice, rabbits, dogs, and monkeys in 1996, it was found to have several toxic effects; in particular, results indicating liver damage in dogs nearly stopped drug development completely. However, favorable results in studies with monkeys and ''in vitro'' human cells allowed testing to continue in humans.
The first clinical trial of Gleevec took place in 1998, after Novartis reluctantly synthesized and released a few grams of the drug for Druker, enough for him to run a trial using a hundred or so patients. The drug received FDA approval in May 2001, only two and a half years after the new drug application was submitted.[ On the same month it made the cover of '']TIME
Time is the continued sequence of existence and events that occurs in an apparently irreversible succession from the past, through the present, into the future. It is a component quantity of various measurements used to sequence events, to ...
'' magazine as a "bullet" to be used against cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award
Lasker-DeBakey Clinical Medical Research Award is one of four annual awards presented by the Lasker Foundation. The Lasker-DeBakey award is given to honor outstanding work for the understanding, diagnosis, prevention, treatment, and cure of diseas ...
in 2009 for "converting a fatal cancer into a manageable chronic condition".
During the FDA review, the tradename of the drug for the US market was changed from "Glivec" to "Gleevec" at the request of the FDA, to avoid confusion with Glyset
Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to break down complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater Diabetes management#Glycemic c ...
, a diabetes drug.
A Swiss patent application was filed on imatinib and various salts on in April 1992, which was then filed in the EU, the US, and other countries in March and April 1993. and in 1996 United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
and European
European, or Europeans, or Europeneans, may refer to:
In general
* ''European'', an adjective referring to something of, from, or related to Europe
** Ethnic groups in Europe
** Demographics of Europe
** European cuisine, the cuisines of Europe ...
patent offices issued patents listing Jürg Zimmermann as the inventor.
In July 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate
In organosulfur chemistry, a mesylate is any salt or ester of methanesulfonic acid (). In salts, the mesylate is present as the anion. When modifying the international nonproprietary name of a pharmaceutical substance containing the group ...
(the mesylate salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...
of imatinib). The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. This is the actual form of the drug sold as Gleevec/Glivec; a salt (imatinib mesylate) as opposed to a free base, and the beta crystalline form as opposed to the alpha or other form. In 1998, Novartis filed international patent applications claiming priority to the 1997 filing. A United States patent was granted in 2005.
Society and culture
Economics
In 2013, more than 100 cancer specialists published a letter in ''Blood'' saying that the prices of many new cancer drugs, including imatinib, are so high that people in the United States couldn't afford them, and that the level of prices, and profits, was so high as to be immoral. Signatories of the letter included Brian Druker, Carlo Gambacorti-Passerini, and John Goldman, developers of imatinib. They wrote that in 2001, imatinib was priced at a year, which was based on the price of interferon, then the standard treatment, and that at this price Novartis would have recouped its initial development costs in two years. They wrote that after unexpectedly becoming a blockbuster, Novartis increased the price to per year in 2012, with annual revenues of $4.7 billion. Other physicians have complained about the cost.
Druker, who led the clinical studies, never received any royalties or profits from the success of the drug.
By 2016, the average wholesale price had increased to a year, according to an analysis prepared for ''The Washington Post
''The Washington Post'' (also known as the ''Post'' and, informally, ''WaPo'') is an American daily newspaper published in Washington, D.C. It is the most widely circulated newspaper within the Washington metropolitan area and has a large nati ...
'' by Stacie Dusetzina of the University of North Carolina at Chapel Hill
A university () is an institution of higher (or tertiary) education and research which awards academic degrees in several academic disciplines. Universities typically offer both undergraduate and postgraduate programs. In the United States ...
. When competitive drugs came on the market, they were sold at a higher price to reflect the smaller population, and Novartis raised the price of Gleevec to match them.
A 2012 economic analysis funded by Bristol-Myers Squibb estimated that the discovery and development of imatinib and related drugs had created $143 billion in societal value at a cost to consumers of approximately $14 billion. The $143 billion figure was based on an estimated 7.5 to 17.5 year survival advantage conferred by imatinib treatment, and included the value (discounted at 3% per annum) of ongoing benefits to society after the imatinib patent expiration.
Prices for a 100 mg pill of Gleevec internationally range from $20 to $30, although generic imatinib is cheaper, as low as $2 per pill.
Controversies
Patent litigation in India
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
fought a seven-year, controversial battle to patent Gleevec in India, and took the case all the way to the Indian Supreme Court
The Supreme Court of India ( IAST: ) is the supreme judicial authority of India and is the highest court of the Republic of India under the constitution. It is the most senior constitutional court, has the final decision in all legal matters ...
. The patent application at the center of the case was filed by Novartis in India in 1998, after India had agreed to enter the World Trade Organization
The World Trade Organization (WTO) is an intergovernmental organization that regulates and facilitates international trade. With effective cooperation
in the United Nations System, governments use the organization to establish, revise, and e ...
and to abide by worldwide intellectual property standards under the TRIPS
The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) is an international legal agreement between all the member nations of the World Trade Organization (WTO). It establishes minimum standards for the regulation by nat ...
agreement. As part of this agreement, India made changes to its patent law, the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions. These changes came into effect in 2005, so Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law in 2005, just before the laws came into effect.
The patent application claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate
In organosulfur chemistry, a mesylate is any salt or ester of methanesulfonic acid (). In salts, the mesylate is present as the anion. When modifying the international nonproprietary name of a pharmaceutical substance containing the group ...
). In 1993, during the time India did not allow patents on products, Novartis had patented imatinib, with salts
In chemistry, a salt is a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions, which results in a compound with no net electric charge. A common example is table salt, with positively c ...
vaguely specified, in many countries but could not patent it in India.[ The key differences between the two patent applications, were that 1998 patent application specified the counterion (Gleevec is a specific salt – imatinib mesylate) while the 1993 patent application did not claim any specific salts nor did it mention mesylate, and the 1998 patent application specified the solid form of Gleevec – the way the individual molecules are packed together into a solid when the drug itself is manufactured (this is separate from processes by which the drug itself is formulated into pills or capsules) – while the 1993 patent application did not. The solid form of imatinib mesylate in Gleevec is beta crystalline.
As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR was granted in November 2003.][Novartis v UoI, para 8–9]
Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India.
When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions
''Oppositions'' was an architectural journal produced by the Institute for Architecture and Urban Studies from 1973 to 1984. Many of its articles contributed to advancing architectural theory and many of its contributors became distinguished practi ...
initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy." At one point, Novartis went to court to try to invalidate Section 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal. Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.
The Supreme Court case hinged on the interpretation of Section 3d. The Supreme Court issued its decision in 2013, ruling that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.
Research
One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis
Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors.
People affected by mas ...
, including those who had the D816V mutation in c-KIT. However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-KIT is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-KIT. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis.
Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension. It was shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension. However, a long-term trial of Imatinib in people with pulmonary arterial hypertension was unsuccessful, and serious and unexpected adverse events were frequent. These included 6 subdural hematoma
A subdural hematoma (SDH) is a type of bleeding in which a collection of blood—usually but not always associated with a traumatic brain injury—gathers between the inner layer of the dura mater and the arachnoid mater of the meninges surround ...
s and 17 deaths during or within 30 days of study end.
In systemic sclerosis
Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two ...
, the drug has been tested for potential use in slowing down pulmonary fibrosis
Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...
. In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
(PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
in mice
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
without or with diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
.
Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox
Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...
, should an outbreak ever occur.
''In vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
'' studies identified that a modified version of imatinib can bind to gamma-secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. Th ...
activating protein ( GSAP). GSAP selectively increases the production and accumulation of neurotoxic beta-amyloid
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which i ...
plaques, which suggests that molecules which target GSAP and are able to cross blood–brain barrier are potential therapeutic agents for treating Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. Another study suggests that imatinib may not need to cross the blood–brain barrier to be effective at treating Alzheimer's, as the research indicates the production of beta-amyloid may begin in the liver. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain. It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms.
A formulation of imatinib with a cyclodextrin
Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical ...
(Captisol) as a carrier to overcome the blood–brain barrier has shown reversal of opioid tolerance in a 2012 study in rats.
Imatinib is an experimental drug in the treatment of desmoid tumor
Aggressive fibromatosis or desmoid tumor is a rare condition. Desmoid tumors arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wou ...
or aggressive fibromatosis
Aggressive fibromatosis or desmoid tumor is a rare condition. Desmoid tumors arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wou ...
.
Etymology
The ''-tinib'' word stem makes reference to the drug's action as a tyrosine kinase (TYK) inhibitor.
See also
*Bcr-Abl tyrosine-kinase inhibitor
Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadel ...
*History of cancer chemotherapy
The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the ...
References
External links
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