Temsirolimus: Difference between revisions

{{Short description|Chemical compound}}

| Verifiedfields = changed

| verifiedrevid = 409344559

| IUPAC_name = (1''R'',2''R'',4''S'')-4-{(2''R'')-2-[(3''S'',6''R'',7''E'',9''R'',10''R'',12''R'',14''S'',15''E'',17''E'',19''E'',21''S'',23''S'',26''R'',27''R'',34a''S'')-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3''H''-23,27-epoxypyrido[2,1-''c''][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

| image = Temsirolimus.svg

<!--Clinical data-->

| tradename = Torisel

| Drugs.com = {{drugs.com|monograph|temsirolimus}}

| MedlinePlus = a607071

| licence_EU = yes

| DailyMedID = Temsirolimus

| licence_US = Torisel

| pregnancy_AU = D

| pregnancy_US = N

| pregnancy_category =

| legal_AU = S4

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Torisel EPAR" />

| legal_status =

| routes_of_administration = [[Intravenous therapy|Intravenous]]

| ATC_prefix = L01

| ATC_suffix = EG01

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound =

| metabolism = [[Liver]]

| elimination_half-life = 17.3 hours (temsirolimus); 54.6 hours (sirolimus)<ref name="a">{{cite book|title=Temsirolimus Drug Monograph|publisher=Cancer Care Ontario |date=June 2014|page=2}}</ref>

| excretion = Urine (4.6%), faeces (78%)<ref name="a"/>

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 162635-04-3

| PubChem = 6918289

| IUPHAR_ligand = 5892

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB06287

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 21468899

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 624KN6GM2T

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201182

| synonyms = CCI-779

<!--Chemical data-->

| C=56 | H=87 | N=1 | O=16

'''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,<ref>{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108924.htm |title=FDA Approves New Drug for Advanced Kidney Cancer |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=May 30, 2007 |access-date=October 15, 2013 |archive-date=October 16, 2012 |archive-url=https://web.archive.org/web/20121016045109/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108924.htm |url-status=dead }}</ref> and was also approved by the [[European Medicines Agency]] (EMA) in November 2007.<ref name="Torisel EPAR">{{cite web | title=Torisel EPAR | website=[[European Medicines Agency]] | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/torisel | access-date=6 November 2020}}</ref> It is a derivative and prodrug of [[sirolimus]].

Temsirolimus is a specific inhibitor of [[mammalian target of rapamycin|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| sirolimus (rapamycin)]] in vivo;<ref>{{cite web|title=Pharmacology Review, Application Number 22-088|last1=Hastings|first1=Kenneth|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022088s000_PharmR.pdf|publisher=FDA|access-date=7 March 2015}}</ref> therefore, its activity may be more attributed to its metabolite rather than the [[prodrug]] itself (despite claims to the contrary by the manufacturer).<ref>{{cite web|title=Temsirolimus Monograph for Professionals|url=https://www.drugs.com/monograph/temsirolimus.html|website=Drugs.com|access-date=7 March 2015}}</ref> Treatment with temsirolimus leads to [[Cell cycle#Inhibitors|cell cycle arrest]] in the [[G1 phase]], and also inhibits [[Angiogenesis#Tumor angiogenesis|tumor angiogenesis]] by reducing synthesis of [[Vascular endothelial growth factor|VEGF]].<ref>{{cite journal | vauthors = Wan X, Shen N, Mendoza A, Khanna C, Helman LJ | title = CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling | journal = Neoplasia | volume = 8 | issue = 5 | pages = 394–401 | date = May 2006 | pmid = 16790088 | pmc = 1592447 | doi = 10.1593/neo.05820 }}</ref>

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.<ref>{{cite journal | vauthors = Rubio-Viqueira B, Hidalgo M | title = Targeting mTOR for cancer treatment | journal = Current Opinion in Investigational Drugs | volume = 7 | issue = 6 | pages = 501–12 | date = June 2006 | pmid = 16784020 }}</ref> 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 ([[HIF1A|HIF-1a]]) are increased. HIF-1a then stimulates [[Vascular endothelial growth factor|VEGF]].<ref>{{cite journal | vauthors = Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT | display-authors = 6 | title = Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin | journal = Molecular and Cellular Biology | volume = 22 | issue = 20 | pages = 7004–14 | date = October 2002 | pmid = 12242281 | pmc = 139825 | doi = 10.1128/MCB.22.20.7004-7014.2002 }}</ref> Whether or not mTOR kinase is activated, determines whether the tumor cell produces key [[protein]]s needed for proliferation, growth, survival, and [[angiogenesis]].<ref>{{cite journal | vauthors = Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M | title = Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus | journal = Cancer Research | volume = 66 | issue = 11 | pages = 5549–54 | date = June 2006 | pmid = 16740688 | doi = 10.1158/0008-5472.CAN-05-2825 | doi-access = }}</ref>

mTOR is activated in tumor cells by various mechanisms including growth factor surface receptor tyrosine kinases, [[oncogene]]s, and loss of [[tumor suppressor gene]]s. These activating factors are known to be important for [[malignant]] transformation and progression.<ref>{{cite journal | vauthors = Dancey JE | title = Therapeutic targets: MTOR and related pathways | journal = Cancer Biology & Therapy | volume = 5 | issue = 9 | pages = 1065–73 | date = September 2006 | pmid = 16969122 | doi = 10.4161/cbt.5.9.3175 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL | display-authors = 6 | title = Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer | journal = Nature Medicine | volume = 12 | issue = 1 | pages = 122–7 | date = January 2006 | pmid = 16341243 | doi = 10.1038/nm1337 | s2cid = 1853822 }}</ref>

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]].<ref>{{cite journal | vauthors = Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ | display-authors = 6 | title = Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma | journal = The New England Journal of Medicine | volume = 356 | issue = 22 | pages = 2271–81 | date = May 2007 | pmid = 17538086 | doi = 10.1056/NEJMoa066838 | doi-access = free }}</ref>

**fatigue

**skin rash

**[[mucositis]]

**[[hemoglobin]] decreased

**[[lymphocyte]]s decreased

**triglycerides increased

**glucose increased

**phosphorus decreased

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.<ref>{{cite journal | vauthors = Choueiri TK, Je Y, Sonpavde G, Richards CJ, Galsky MD, Nguyen PL, Schutz F, Heng DY, Kaymakcalan MD | display-authors = 6 | title = Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors | journal = Annals of Oncology | volume = 24 | issue = 8 | pages = 2092–7 | date = August 2013 | pmid = 23658373 | doi = 10.1093/annonc/mdt155 | doi-access = free }}

*{{cite web |author=Charles Bankhead |date=February 17, 2013 |title=Fatal AEs Higher with mTOR Drugs in Cancer |website=[[MedPage Today]] |url=http://www.medpagetoday.com/MeetingCoverage/MGUCS/37404}}</ref>

==Lung toxicity==

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.<ref>{{cite journal | vauthors = Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, Pond GR, Seymour L, Niroumand M | display-authors = 6 | title = Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus | journal = European Journal of Cancer | volume = 42 | issue = 12 | pages = 1875–80 | date = August 2006 | pmid = 16806903 | doi = 10.1016/j.ejca.2006.03.015 }}</ref> The risk of interstitial lung disease is increased with temsirolimus doses greater than 25&nbsp;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.<ref name="c">{{cite book|title=Temsirolimus Drug Monograph|publisher=Cancer Care Ontario |date=June 2014|page=4}}</ref>

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&nbsp;mg diphenhydramine, 30 minutes prior to administration) is recommended to minimize the risk of an allergic reaction.<ref name="b">{{cite journal | vauthors = Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A | title = Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features | journal = Annals of Oncology | volume = 19 | issue = 8 | pages = 1387–92 | date = August 2008 | pmid = 18385198 | doi = 10.1093/annonc/mdn066 | doi-access = free }}</ref><ref name="c"/>

== See also ==

*[[Discovery and development of mTOR inhibitors]]

== References ==

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/temsirolimus | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Temsirolimus }}

{{Extracellular chemotherapeutic agents}}

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[[Category:Drugs developed by Wyeth]]

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