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Tyrosine kinase inhibitors are drugs used in cancer therapy. The action of this group of substances is based on blocking a specific type of enzymes - tyrosine kinases. Studies from the last 30 years have shown that these enzymes show increased activity within neoplastic lesions. Tyrosine kinase inhibitors are used in targeted therapy against cancer cells.

Tyrosine kinase inhibitors(TKI, tyrosine kinase inhibitors) belong to the group of molecularly targeted drugs and are used in the treatment of cancer. When used as part of targeted therapy, they act selectively and give significantly fewer side effects.

What is cancer pharmacotherapy?

The basic method of pharmacological treatment of neoplastic changes is chemotherapy. As a result of damage, neoplastic cells can divide in an unlimited way. They are also not subject to the natural cell death program, or apoptosis. The mechanism of action of drugs from this group is based on blocking cell division and initiating their death.

The main problem with chemotherapy is that cytostatic drugs are toxic to both sick and he althy cells. They block cell division throughout the body. They damage especially those tissues in which large amounts of new cells are produced, e.g. bone marrow. This mechanism is responsible for the serious side effects of chemotherapy.

Currently, the search for new anti-cancer drugs focuses on substances that will be harmful to cancer cells as much as possible, while not destroying he althy ones. Thanks to the great advances in the field of molecular biology, it has become possible to create drugs that work differently from classical cytostatics. This new approach has been called targeted therapy.

Targeted therapy works by blocking the pathway of signals that stimulate division in cancer cells. It focuses on specific damage to information transmission, not the cell division itself. Thanks to this approach, new drugs are more selective against cancer cells than classic cytostatics. Tyrosine kinase inhibitors are such preparations.

How do neoplastic changes arise?

Cancer cells are formed onthe effect of mutations in DNA, i.e. the genetic material that contains information about their proper functioning. However, not all of its damage leads to the formation of cancer. The change must be about information about the life cycle and the division. He althy cells divide when they receive the signal that it is needed. If they are damaged, they undergo apoptosis, or programmed death. Cancer cells do not have this regulation and therefore divide uncontrollably.

DNA mutations can arise spontaneously. However, neoplastic changes are most often caused by an external factor. These can be chemical mutagens, i.e. various types of toxic substances that have a toxic effect on the genetic material. For example, such toxins are contained in cigarette smoke. There are also physical mutagens. This group includes various types of radiation, e.g. UV.

The ability to induce neoplastic changes is also possessed by oncogenic viruses. This is because of the way they multiply in human cells. Viruses introduce their genetic material into our DNA, causing changes in it. Studies have shown that sometimes these modifications are made to the synthesis of tyrosine kinases. Changes of this type disturb the body's control over cycles of cell division.

What is the function of tyrosine kinases?

Tyrosine kinases are enzymes that act as regulatory proteins. They are used to transmit information about the basic functions of a cell, such as growth, movement or division. Tyrosine kinases damaged by mutations send false information, leading to the formation of neoplastic changes.

These enzymes can be divided into two groups: receptor kinases located on cell membranes and cytoplasmic kinases located inside the cell. Receptor proteins in membranes receive information from outside the cell in the form of chemical molecules that attach to them. Such information could be, for example, a call to start cell division.

Intracellular tyrosine kinases are responsible for transmitting a signal from receptor proteins into the cell. The stimulation of kinases triggers a protein cascade that leads to signal transduction to the cell nucleus. If it is information about the initiation of cell division, it will be started after it is transmitted by cytoplasmic kinases that were previously stimulated by receptor kinases. This regulatory system ensures that all he althy cells in the body function efficiently.

What are the effects of damage to the tyrosine kinase function?

Mutation can lead todisturbances of this way of transmitting information in the cell. Mutant tyrosine kinases continuously convey information about the initiation of cell division. They are not regulated by signaling molecules. This leads to the uncontrolled multiplication of cells and hence the formation of neoplastic changes.

It has been shown that many malignant neoplasms, including leukemia, exhibit increased activity of tyrosine kinases. The mutated proteins in these neoplastic lesions absorb and transmit signals too intensively. This leads to disruption of cellular processes such as multiplication and programmed death.

A dysregulation can also occur through auto-secretory enzyme activation. Due to a mistake, tyrosine kinase stimulates the synthesis of its own activator protein. This protein activates a kinase that re-stimulates activator synthesis. This creates a self-reinforcing reaction loop. This type of error in the functioning of tyrosine kinases has been observed in breast cancer, ovarian cancer, bladder cancer, and brain cancer, among others.

How do tyrosine kinase inhibitors work?

The mechanism of action of tyrosine kinase inhibitors is based on the attachment of these drugs to the active center of the enzyme. In this way, the drug blocks the activation of tyrosine kinase. The consequence is that the transmission of information to the kernel about the start of a new partition is stopped.

Tyrosine kinase inhibitors are effective drugs. They show selectivity against neoplastic cells, therefore they cause less side effects than classic cytostatic drugs. The advantage of these drugs is also that most of them are orally. This increases the comfort of admission and eliminates complications related to intravenous administration. Their safety of use as well as the synergistic effect makes them suitable for use together with classic cytostatics.

Tyrosine kinase inhibitors are now successfully used in cancer therapy. Research into new drugs from this group is still ongoing. Many tyrosine kinase inhibitors are under clinical development.

Tyrosine kinase inhibitors are divided into non-receptor and receptor drugs.

Non-receptor tyrosine kinase inhibitors

Drugs from this group are particularly active against cancer cells of chronic myeloid leukemia and acute lymphocytic leukemia. This therapeutic group includes:

  • imatinib - the first registered drug that blocks the activity of tyrosine kinases. It is used in the treatment of leukemia and inoperable cancers of the gastrointestinal tract. Treatment with imatinib allows you to achievea high percentage of remission with relatively low toxic effects. The biggest problem with therapy with this drug is resistance. It may develop during treatment, but neoplastic lesions may also be primary resistant to imatinib in some patients. This applies to 20-30% of patients undergoing treatment for the first time
  • dasatinib - is used in the treatment of chronic myeloid leukemia in the case of imatinib resistance
  • nilotinib - also used in imatinib resistance

Receptor tyrosine kinase inhibitors

This group of drugs includes inhibitors of receptor kinases located on the surface of cell membranes. Depending on the type of receptor on which the inhibitor acts, it can be divided into three types:

Epidermal growth factor receptor inhibitorsare used in the treatment of malignant neoplasms, e.g. colorectal, cervical, lung or prostate cancer.

  • gefitinib
  • erlotynib
  • lapatinib

Vascular endothelial growth factor receptor inhibitorsblock the formation of new blood vessels in neoplastic lesions. Almost all neoplastic tumors secrete vascular endothelial growth factor in response to oxygen deficiency. It stimulates the formation of blood vessels in the neoplastic area. This allows oxygenation of the tumor and its further enlargement. By using inhibitors of the appropriate tyrosine kinases, this process can be blocked. This group of drugs includes:

  • semaxinib
  • vatalanib
  • sunitynib
  • sorafenib

Platelet growth factor receptor inhibitorsare used to treat myeloid leukemia, glioblastoma and many other cancers. They are also used as immunosuppressants in rheumatoid arthritis. This group includes: tandutinibleflunomid

Side effects of tyrosine kinase inhibitors

Adverse effects of these drugs are observed in over 70% of patients. Fortunately, they usually have a moderate to mild level of severity. Interstitial pneumonia is a serious complication of the therapy, but it occurs very rarely. The most common side effects:

  • diarrhea
  • skin changes
  • weakness
  • liver dysfunction
About the authorSara Janowska, MA in pharmacyPhD student of interdisciplinary doctoral studies in the field of pharmaceutical and biomedical sciences carried out at the Medical University ofLublin and the Institute of Biotechnology in Białystok. A graduate of pharmaceutical studies at the Medical University of Lublin with a specialization in Plant Medicine. She obtained a master's degree defending a thesis in the field of pharmaceutical botany on the antioxidant properties of extracts obtained from twenty species of mosses. Currently, in his research work, he deals with the synthesis of new anti-cancer substances and the study of their properties on cancer cell lines. For two years she worked as a master of pharmacy in an open pharmacy.

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