|
| Primary information |
|---|
| ID | 13447 |
| Therapeutic ID | Th1404 |
| Protein Name | Tasonermin |
| Sequence | >Th1404_Tasonermin
VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
|
| Molecular Weight | 17724 |
| Chemical Formula | NA |
| Isoelectric Point | 6.7 |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | Tasonermin has a terminal half life of 20-30 min at doses of 150 µg/m² [L1339]. This value increases as dosage increases. |
| Description | Tasonermin is recombinant soluble form tumor necrosis factor α produced via _Escherichia coli_ cell culture. It was approved for use by the European Medicines Agency in April of 1999 for use as an adjunt to surgery for the subsequent removal of the tumor and in palliative care for irresectable soft tissue sarcoma of the limbs as the product Beromun. It is administered with [DB01042] via mild hyperthermic isolated limb perfusion. |
| Indication/Disease | For use in adults as an adjunct to surgery for subsequent removal of the tumour so as to prevent or delay amputation, or in palliative care, for irresectable soft tissue sarcoma of the limbs [FDA Label]. Used in combination with melphalan via mild hyperthermic isolated limb perfusion. |
| Pharmacodynamics | Tasonermin is thought to contribute to the destruction of tumor tissue via several direct and indirect effects [FDA Label]. Tasonermin directly inhibits cell proliferation in a variety of cancer cells. It also modifies endothelial cell morphology and reduces their proliferation in tumor microvasculature. Modification of the expression of cell adhesion proteins, proteins affecting coagulation, interleukins, and hematopoietic growth factors favors a procoagulant state resulting in microvascular thrombosis. These changes also increase infiltration of the tumor tissue by leukocytes. Monocytes, macrophages, and granulocytes are activated allowing better adherence to the endothelium and subjecting the tumor cells to phagocytosis and respiratory bursts as well as producing degranulation of immune cells to further enhance inflammatory activity. Active antigen presenting cells are able to activate and induce proliferation of T- and B-lymphocyte cells to allow the adaptive immune system to contribute to tumor cell damage. These changes lead to hemorraghic necrosis of the tumor. |
| Mechanism of Action | Since tasonermin is recombinant TNF-α, it functions exactly as endogenous TNF-α does. The direct cytotoxic effect of TNF-α is mediated by TNF-α receptor 1 [A31954]. The bound receptor activates the well-reviewed death receptor pathway involving the activation of initiator caspases 8 and 9 then ultimately ending in the activation of effector caspase 3 which begins the process of apoptosis. The effect on tumor vasculature is mediated by the inflammatory signalling pathway of TNF-α, the NFκB pathway [A31954]. This pathway is also activated by TNFR1 when bound to TNFα. The NFκB transcription factor increases expression of proteins in vascular endothelial cells. These proteins include cell adhesion molecules, inflammatory mediators like prostaglandins and interleukins, and growth factors [A31958]. TNF-&alpha also increases the expression of inducible nitric oxide synthase via this pathway which contributes to the generation of reactive nitrogen species [A31956]. These species are able to damage cells in the tumor and microvasculature. The cytokines produced from NFκB activation and TNF-&aplha; itself serve to activate the cells of the immune system which further damage tumor cells with respiratory bursts, phagocytosis and subsequent breakdown of the cell, and release of cytotoxic enzymes. The antigen presenting cells which phagocytose the tumor cells are able to activate lymphocytes and allow the adaptive immune system to further damage the tumor tissue [T116]. |
| Toxicity | In addition to its intended cytotoxic effects, tasonermin produces secondary adverse effects. Studies in mice, rats, dogs, monkeys, and rabbits observed hematological changes including anemia, increased hematocrit, and changes in leukocyte and platelet counts dependent on species and treatment duration [FDA Label]. Tasonermin also produces decreases in blood pressure. Increases in heart rate and reductions in cardiac contractility have been noted in some studies. Increased liver enzymes suggest altered liver function as a result of tasonermin administration. Changes in kidney function have also been observed including increased water and sodium excretion as well as increased serum urea and creatinine. The only study to determine a no observable adverse effect level found the value to be 0.1 µg/kg in monkeys during a 7-day course of tasonermin. |
| Metabolism | No metabolism data is available. Tasonermin is assumed to be broken down similarly to other proteins in systemic circulation. |
| Absorption | No absorption data is available. No enteral route formulation exists for tasonermin. |
| The estimated volume of distribution varies with the dose administered with intravenous doses of 35 µg/m² and 150 µg/m² producing values of 55 L and 17 L respectively [L1339]. |
| Clearance | Clearance was estimated to be 2 L/min and 0.5 L/min after intravenous doses of 35 µg/m² and 150 µg/m² respectively [L1339]. This value decreases as dosage increases. |
| Categories | Adjuvants, Immunologic |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Tumor necrosis factor receptor superfamily member 1A,Tumor necrosis factor receptor superfamily member 1B |
| Brand Name | Beromun |
| Company | Belpharma S.A. |
| Brand Description | Belpharma S.A. |
| Prescribed For | NA |
| Chemical Name | 1 mg/5ml |
| Formulation | NA |
| Physical Appearance | Most patients taking Beromun experience fever, which is usually mild to moderate. Other side effects seen very commonly (in more than 1 patient in 10) are infection, cardiac arrhythmia (unstable heartbeat), nausea (feeling sick), vomiting, liver damage, fatigue (tiredness), chills, pain in the limb, nerve injury, skin reactions, oedema (swelling) and wound infection. Some side effects of Beromun are serious and could require a patient to spend time in an intensive-care unit after treatment. |
| Route of Administration | Beromun is a powder and solvent that are made up into a solution for infusion. It contains the active substance tasonermin. |
| Recommended Dosage | Beromun is used in patients with soft-tissue sarcoma (a type of cancer) of the limb (arm or leg), together with melphalan (an anticancer medicine), using a technique called ‘isolated-limb perfusion’ (ILP): both medicines are injected into the limb while the blood circulation in the limb is kept isolated (cut off) from the rest of the body. It can be used before surgery to reduce the size of a tumour, or instead of surgery when the tumour cannot be removed by surgery alone. |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |