Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007,[3] and was also approved by the European Medicines Agency (EMA) in November 2007.[1] It is a derivative and prodrug of sirolimus.
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| Trade names | Torisel |
| Other names | CCI-779 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a607071 |
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| Routes of administration | Intravenous |
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| Metabolism | Liver |
| Elimination half-life | 17.3 hours (temsirolimus); 54.6 hours (sirolimus)[2] |
| Excretion | Urine (4.6%), faeces (78%)[2] |
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| ECHA InfoCard | 100.211.882 |
| Chemical and physical data | |
| Formula | C56H87NO16 |
| Molar mass | 1030.303 g·mol−1 |
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Mechanism of action
editTemsirolimus 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;[4] therefore, its activity may be more attributed to its metabolite rather than the prodrug itself (despite claims to the contrary by the manufacturer).[5] Treatment with temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reducing synthesis of VEGF.[6]
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.[7] 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.[8] Whether or not mTOR kinase is activated, determines whether the tumor cell produces key proteins needed for proliferation, growth, survival, and angiogenesis.[9]
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.[10] 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.[11]
Efficacy
editIn 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.[12]
Adverse reactions
editThe toxicity profile is based on what was found in the phase III trial.[13]
- adverse reaction
- fatigue
- skin rash
- mucositis
- hematologic abnormalities
- hemoglobin decreased
- lymphocytes decreased
- 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.[14]
Lung toxicity
editTemsirolimus 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.[15] 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.[16]
Dosing
editAlthough 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.[13][16]
See also
editReferences
edit- ^ a b "Torisel EPAR". European Medicines Agency. 17 September 2018. Retrieved 6 November 2020.
- ^ a b Temsirolimus Drug Monograph. Cancer Care Ontario. June 2014. p. 2.
- ^ "FDA Approves New Drug for Advanced Kidney Cancer" (Press release). U.S. Food and Drug Administration (FDA). May 30, 2007. Archived from the original on October 16, 2012. Retrieved October 15, 2013.
- ^ Hastings, Kenneth. "Pharmacology Review, Application Number 22-088" (PDF). FDA. Retrieved 7 March 2015.
- ^ "Temsirolimus Monograph for Professionals". Drugs.com. Retrieved 7 March 2015.
- ^ Wan X, Shen N, Mendoza A, Khanna C, Helman LJ (May 2006). "CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling". Neoplasia. 8 (5): 394–401. doi:10.1593/neo.05820. PMC 1592447. PMID 16790088.
- ^ Rubio-Viqueira B, Hidalgo M (June 2006). "Targeting mTOR for cancer treatment". Current Opinion in Investigational Drugs. 7 (6): 501–12. PMID 16784020.
- ^ Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. (October 2002). "Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin". Molecular and Cellular Biology. 22 (20): 7004–14. doi:10.1128/MCB.22.20.7004-7014.2002. PMC 139825. PMID 12242281.
- ^ Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M (June 2006). "Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus". Cancer Research. 66 (11): 5549–54. doi:10.1158/0008-5472.CAN-05-2825. PMID 16740688.
- ^ Dancey JE (September 2006). "Therapeutic targets: MTOR and related pathways". Cancer Biology & Therapy. 5 (9): 1065–73. doi:10.4161/cbt.5.9.3175. PMID 16969122.
- ^ Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, et al. (January 2006). "Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer". Nature Medicine. 12 (1): 122–7. doi:10.1038/nm1337. PMID 16341243. S2CID 1853822.
- ^ Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. (May 2007). "Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma". The New England Journal of Medicine. 356 (22): 2271–81. doi:10.1056/NEJMoa066838. PMID 17538086.
- ^ a b Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A (August 2008). "Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features". Annals of Oncology. 19 (8): 1387–92. doi:10.1093/annonc/mdn066. PMID 18385198.
- ^ Choueiri TK, Je Y, Sonpavde G, Richards CJ, Galsky MD, Nguyen PL, et al. (August 2013). "Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors". Annals of Oncology. 24 (8): 2092–7. doi:10.1093/annonc/mdt155. PMID 23658373.
- Charles Bankhead (February 17, 2013). "Fatal AEs Higher with mTOR Drugs in Cancer". MedPage Today.
- ^ Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, et al. (August 2006). "Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus". European Journal of Cancer. 42 (12): 1875–80. doi:10.1016/j.ejca.2006.03.015. PMID 16806903.
- ^ a b Temsirolimus Drug Monograph. Cancer Care Ontario. June 2014. p. 4.
External links
edit- "Temsirolimus". Drug Information Portal. U.S. National Library of Medicine.
