Sunitinib

Sunitinib is a cancer drug and is used for gastrointestinal stromal tumors (GIST), neuroendocrine tumors of the pancreas or kidney cell tumors that can no longer be surgically removed. It is marketed under the trade name Sutent® and is manufactured by Pfizer. Sunitinib can cause several side effects by interacting with the thyroid hormones.

What is Sunitinib?

Sunitinib is a so-called receptor tyrosine kinase inhibitor and is used in the treatment of special forms of cancer that can no longer be surgically treated. The active substance in sunitinib contains an aromatic skeleton with a complex chemical structure. Its chemical molecular formula is C22H27FN4O2.

Sunitinib is used as a substitute 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. The corresponding proteins are significantly influenced in their activity. Receptor tyrosine kinases mediate entire signal cascades within the cell.

At the same time, they also have an impact on cell proliferation, i.e. H. on the multiplication of cells through cell division, in that they also act as receptors for growth factors. These are especially the growth factors VEGF, PDGF, c-Kit, FLT, RET or CSF. VEGF (Vascular Endothelial Growth Factor) acts as a signaling molecule and 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. In particular, the protein c-kit mediates cell proliferation for stem cells.

All other growth factors also play a major role in cell division. If they are formed to a greater extent, cell division is also stimulated and a cancerous tumor can develop. The growth factors mentioned above play a role in the development of gastrointestinal stromal tumors (GIST), neuroendocrine tumors (NET) of the pancreas and renal cell carcinomas.

GISTs are rare tumors of the connective tissue within the digestive tract. Neuroendocrine tumors are also rare and stimulate the production of certain hormones. By blocking the growth factor receptors, the drug sunitinib can restrict their activity and thus inhibit cancer growth.

Pharmacological effect

Sunitinib has an inhibitory effect on the growth of certain cancer cells. This is especially true for connective tissue cells in the digestive tract, in the kidneys and in neuroendocrine tumors. The active ingredient blocks the so-called receptor tyrosine kinases.

Tyrosine kinases are enzymes that transfer the 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 phosphorylized sites and thus enable the transmission of signals.

An SH2 domain is a characteristic protein segment with approx. 100 amino acids. Due to this binding, a conformational change occurs in the protein, which is passed on to other proteins. A signal cascade develops from this. The receptor tyrosine kinases phosphorylize receptor proteins, which serve as docking points for proteins, which are then activated due to the binding and further mediate certain effects. These proteins also include the growth factors that are responsible for the proliferation of cells. With increased formation of growth factors, cell growth can get out of control, causing cancer to develop.

However, since the growth factors can only develop their effect when they bind to their receptors, their inhibition can help stop the growth of the cancerous tumors.

The receptor is in turn enabled to bind to the growth factors due to the phosphorylation by the receptor tyrosine kinases. However, when the receptor tyrosine kinases are blocked by the drug sunitinib, no binding with the growth factors takes place. Thus the growth factors remain inactive and do not send any signal for cell growth. In the case of cancerous tumors, this means a growth stop or slowed growth.

Medical application & use

As already described, the drug sunitinib is used in special cancers such as gastrointestinal stromal tumors (GIST), neuroendocrine tumors in the pancreas or renal cell carcinoma. There, however, it is only used for inoperable cancer tumors or the formation of metastases.

Furthermore, Sunitinib serves as a substitute preparation if therapy with the drug Imatinib leads to severe side effects. Studies have shown that it works particularly well on the tumors mentioned. The life expectancy of patients treated with sunitinib could be doubled compared to untreated patients in some cases. Furthermore it could be shown that the quality of life of the treated persons improves significantly.

Sunitinib works a long time after it is taken. It has a half-life of around 40 to 60 hours. In the organism it is metabolized by the enzyme CYP3A4 (cytochrome P450 3A4) and thus gains even more effectiveness. The metabolite acts even longer than the active ingredient itself.

Risks & side effects

There are side effects when using sunitinib. Fatigue, diarrhea, high blood pressure, nosebleeds, inflammation of the oral mucosa or the so-called hand-foot syndrome are observed. The hand-foot syndrome causes painful redness and swelling on the soles of the feet and palms. Usually this syndrome is a reaction of the body to the administration of cytotoxic drugs.

Another side effect of sunitinib is the inhibition of the enzyme thyroid peroxidase. Thyroid peroxidase is responsible for the incorporation of iodine into tyrosine to form the thyroid hormones T3 and T4. This can lead to an underactive thyroid gland during treatment with sunitinib. The often observed tiredness during chemotherapy with sunitinib is probably due to this.

Sunitinib must not be used in case of hypersensitivity to the active substance.