Temsirolimus

Overview

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, and was also approved by the European Medicines Agency (EMA) in November 2007. It is a derivative and prodrug of sirolimus.[1][2] WP

Uses, dosage and effects

Dosing

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.[3][4] WP

Risks and side effects

Adverse reactions

The toxicity profile is based on what was found in the phase III trial.[3] WP

• adverse reaction[3] WP
• fatigue[3] WP
• skin rash[3] WP
• mucositis[3] WP
• hematologic abnormalities[3] WP
• hemoglobin decreased[3] WP
• lymphocytes decreased[3] WP
• laboratory abnormalities[3] WP
• triglycerides increased[3] WP
• glucose increased[3] WP
• phosphorus decreased[3] WP

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.[5][6] WP

Pharmacology

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.[7][8][9] WP

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.[10][11][12] WP

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.[13][14] WP

Chemistry

Formula

C56H87NO16 PC

CAS number

162635-04-3 PC

Molar mass (g/mol)

1030.3 PC

IUPAC name (computed by PubChem)

[(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate PC

SMILES

C[C@@H]1CC[C@H]2C[C@@H](/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)OC(=O)C(C)(CO)CO)C)/C)O)OC)C)C)/C)OC PC

InChIKey

CBPNZQVSJQDFBE-FUXHJELOSA-N PC

PubChem CID

6918289

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency FDA Approves New Drug for Advanced Kidney Cancer. May 30, 2007
2. Journal / agency Torisel EPAR. 17 September 2018
3. Journal / agency Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Annals of Oncology. August 2008. doi:10.1093/annonc/mdn066 · PMID 18385198
4. Other Temsirolimus Drug Monograph. June 2014
5. Journal / agency Choueiri TK, Je Y, Sonpavde G, Richards CJ, Galsky MD, Nguyen PL, Schutz F, Heng DY, Kaymakcalan MD. Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors. Annals of Oncology. August 2013. doi:10.1093/annonc/mdt155 · PMID 23658373
6. Other Charles Bankhead. Fatal AEs Higher with mTOR Drugs in Cancer. February 17, 2013
7. Journal / agency Hastings, Kenneth. Pharmacology Review, Application Number 22-088
8. Other Temsirolimus Monograph for Professionals
9. Journal / agency Wan X, Shen N, Mendoza A, Khanna C, Helman LJ. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia. May 2006. doi:10.1593/neo.05820 · PMID 16790088 · PMC1592447
10. Journal / agency Rubio-Viqueira B, Hidalgo M. Targeting mTOR for cancer treatment. Current Opinion in Investigational Drugs. June 2006. PMID 16784020
11. Journal / agency Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology. October 2002. doi:10.1128/MCB.22.20.7004-7014.2002 · PMID 12242281 · PMC139825
12. Journal / agency Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Research. June 2006. doi:10.1158/0008-5472.CAN-05-2825 · PMID 16740688
13. Journal / agency Dancey JE. Therapeutic targets: MTOR and related pathways. Cancer Biology & Therapy. September 2006. doi:10.4161/cbt.5.9.3175 · PMID 16969122
14. Journal / agency Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Medicine. January 2006. doi:10.1038/nm1337 · PMID 16341243

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.