Sunitinib is an anticancer drug and is used for gastrointestinal stromal tumors (GIST) that can no longer be surgically removed, neuroendocrine tumors of the pancreas, or renal cell tumors. It is marketed under the trade name Sutent and is manufactured by Pfizer. Sunitinib can cause various side effects by interacting with thyroid hormones.
What is sunitinib?
Sunitinib is used to treat specific forms of cancer that are no longer treatable by surgery. Sunitinib is a so-called receptor tyrosine kinase inhibitor and is used in the treatment of special forms of cancer that are no longer surgically treatable. The active ingredient of sunitinib contains an aromatic backbone with a complicated chemical structure. Its chemical molecular formula is C22H27FN4O2. Sunitinib serves as a replacement drug if treatment with imatinib is not tolerated. Imatinib is also a receptor tyrosine kinase inhibitor. Receptor tyrosine kinases are responsible for the transfer of phosphate groups to the tyrosine residues within a protein. In this process, the activity of the corresponding proteins is significantly influenced. Receptor tyrosine kinases thus mediate entire signaling cascades within the cell. At the same time, they also influence cell proliferation, i.e. the multiplication of cells through cell division, by also acting as receptors for growth factors. These are especially the growth factors VEGF, PDGF, c-Kit, FLT, RET or CSF. VEGF (Vascular Endothelial Growth Factor), as a signal molecule, stimulates the formation of blood vessels (vasculogenesis). The growth factor PDGF (Platelet Derived Growth Factor) acts as a mitogen (stimulator of cell division) especially for cells of the connective tissue. The protein c-Kit mediates cell proliferation for stem cells in particular. All other growth factors also play a major role in cell division. When they are produced in increased amounts, cell division is also stimulated and a cancerous tumor may form. Thus, the above growth factors play a role in the development of gastrointestinal stromal tumors (GIST), pancreatic neuroendocrine tumors (NET), and renal cell carcinoma. GISTs are rare tumors of connective tissue within the digestive tract. Neuroendocrine tumors are equally rare and stimulate the production of certain hormones. The drug sunitinib, by blocking growth factor receptors, can limit their activity and thus inhibit cancer growth.
Pharmacologic action
Sunitinib thus has an inhibitory effect on the growth of certain cancer cells. This is particularly true for connective tissue cells in the digestive tract, kidneys, and neuroendocrine tumors. The active ingredient blocks the so-called receptor tyrosine kinases. Tyrosine kinases are enzymes that transfer phosphate groups to the tyrosine residues of other proteins. The phosphorylated sites of the protein are recognized by the SH2 domains of other proteins. They bind to the phosphorylated sites, enabling the transfer of signals. An SH2 domain is a characteristic protein segment of about 100 amino acids. Due to this binding, a conformational change of the protein occurs, which is passed on to other proteins. A signaling cascade develops from this. The receptor tyrosine kinases phosphorylate receptor proteins, which serve as docking sites for proteins that are then activated as a result of the binding and further mediate certain effects. These proteins include growth factors, which are responsible for cell proliferation. If the formation of growth factors is increased, cell growth can get out of control, with cancer developing. However, since growth factors can only exert their effect when they bind to their receptors, their inhibition can contribute to the growth arrest of cancerous tumors. In turn, the receptor is enabled to bind with the growth factors due to phosphorylation by the receptor tyrosine kinases. However, when the receptor tyrosine kinases are blocked by the drug sunitinib, binding with the growth factors does not occur. Thus, the growth factors remain inactive and do not send a signal for cell growth. In the case of cancer tumors, this means growth arrest or slowed growth.
Medical application and use
As described earlier, the drug sunitinib is used in specific cancers such as gastrointestinal stromal tumors (GIST), pancreatic neuroendocrine tumors, or renal cell carcinoma. There, however, it is only used for inoperable cancer tumors or metastatic disease. Furthermore, sunitinib serves as a replacement drug when therapy with the drug imatinib leads to severe side effects. Studies have shown that it is particularly effective in the treatment of these tumors. In some cases, the life expectancy of patients treated with sunitinib was doubled compared to untreated patients. Furthermore, it has been shown that the quality of life of treated individuals improves significantly. Sunitinib has a very long effect after it is taken. It has a half-life of approximately 40 to 60 hours. In the organism, it is metabolized by the enzyme CYP3A4 (cytochrome P450 3A4) and thus gains even more efficacy. The metabolite thus acts even longer than the active ingredient itself.
Risks and side effects
Side effects may occur with the use of sunitinib. Thus, fatigue, diarrhea, high blood pressure, nosebleeds, inflammation of the oral mucosa, or the so-called hand-foot syndrome is observed. In hand-foot syndrome, there is painful redness and also swelling on the soles of the feet and palms of the hands. Most often, this syndrome is a reaction of the body to the administration of cytostatic drugs. Another side effect of sunitinib is inhibition of the enzyme thyreoperoxidase. Thyreoperoxidase is responsible for the incorporation of iodine into tyrosine to form the thyroid hormones T3 and T4. This can lead to hypothyroidism during treatment with sunitinib. The fatigue often observed during chemotherapy with sunitinib is probably due to this. Sunitinib should not be used in the presence of hypersensitivity to the active ingredient.
