|Drug class||mTOR inhibitor|
|Main uses||Renal cell carcinoma (RCC), mantle cell lymphoma|
|Side effects||Pneumonia, low platelets, low red blood cells, high blood sugar, difficulty breathing, vomiting, rash, swelling, tiredness, fever|
|Typical dose||25 to 75 mg once weekly|
|Elimination half-life||17.3 hours (temsirolimus); 54.6 hours (sirolimus)|
|Excretion||Urine (4.6%), faeces (78%)|
|Chemical and physical data|
|Molar mass||1030.303 g·mol−1|
|(what is this?)|
Temsirolimus, sold under the brand name Torisel, is a medication used to treat renal cell carcinoma (RCC) and mantle cell lymphoma. It is given by gradual injection into a vein. It is generally used together with an antihistamine such as diphenhydramine.
Common side effects include infections such as pneumonia, low platelets, low red blood cells, high blood sugar, difficulty breathing, vomiting, rash, swelling, tiredness, and fever. Serious side effects may include allergies, pulmonary embolism, and high blood fat. It is converted in the body to sirolimus; which works by blocking a protein called mTOR.
Temsirolimus was approved for medical use in the United States and Europe in 2007. In the United States it costs about 1,900 USD per 25 mg dose as of 2021. This amount in the United Kingdom costs the NHS about £620.
In an international three-arm phase III study with 626 previously untreated, poor-prognosis patients, temsirolimus, interferon-α and the combination of both agents was compared. Median overall survival improved significantly in the temsirolimus group (10.9 months) compared with interferon-α group (7.3 months) and the combination group (8.4 months). Further studies are needed to determine the role of temsirolimus in the first-line treatment of patients with a more favorable prognosis, how it can be combined with other targeted agents and as sequential therapy with sunitinib or sorafenib.
For renal cell carcinoma a dose of 25 mg per week is generally used.
For mental cell lymphoma the typically dose is 175 mg per week for three weeks and than 75 mg per week.
Although infusion reactions can occur while temsirolimus is being administered, most hypersensitivity reactions occurring on the same day as temsirolimus administration were not severe. Antihistamine pretreatment (e.g. 25–50 mg diphenhydramine, 30 minutes prior to administration) is recommended to minimize the risk of an allergic reaction.
The toxicity profile is based on what was found in the phase III trial.
- adverse reaction
- skin rash
- hematologic abnormalities
- laboratory abnormalities
- triglycerides increased
- glucose increased
- phosphorus decreased
Temsirolimus has been generally well tolerated in clinical settings by patients with advanced RCC. In patients with RCC, the adverse effect profile of temsirolimus is primarily metabolic in nature, with minimal impact on QoL compared with the commonly seen side-effects with oral multikinase inhibitors. Temsirolimus’ high level of specificity for mTOR likely contributes to the tolerability of temsirolimus. However, temsirolimus increases mortality in cancer patients.
Temsirolimus is associated with lung toxicity, and the risk of developing this complication may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease. The risk of interstitial lung disease is increased with temsirolimus doses greater than 25 mg, symptoms of which may include dry cough, fever, eosinophilia, chest pain, and dyspnea on exertion. Toxicity usually occurred early (within days to weeks) or late (months to years) after treatment.
Mechanism of action
Temsirolimus is a specific inhibitor of mTOR and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells. Though temsirolimus shows activity on its own, it is also known to be converted to sirolimus (rapamycin) in vivo; therefore, its activity may be more attributed to its metabolite rather than the prodrug itself (despite claims to the contrary by the manufacturer). Treatment with temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reducing synthesis of VEGF.
mTOR (mammalian target of rapamycin) is a kinase enzyme inside the cell that collects and interprets the numerous and varied growth and survival signals received by tumor cells. When the kinase activity of mTOR is activated, its downstream effectors, the synthesis of cell cycle proteins such as cyclin D and hypoxia-inducible factor-1a (HIF-1a) are increased. HIF-1a then stimulates VEGF. Whether or not mTOR kinase is activated, determines whether the tumor cell produces key proteins needed for proliferation, growth, survival, and angiogenesis.
mTOR is activated in tumor cells by various mechanisms including growth factor surface receptor tyrosine kinases, oncogenes, and loss of tumor suppressor genes. These activating factors are known to be important for malignant transformation and progression. mTOR is particularly important in the biology of renal cancer (RCC) owing to its function in regulating HIF-1a levels. Mutation or loss of the von Hippel Lindau tumor-suppressor gene is common in RCC and is manifested by reduced degradation of HIF-1a. In RCC tumors, activated mTOR further exacerbates accumulation of HIF-1a by increasing synthesis of this transcription factor and its angiogenic target gene products.
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