Temsirolimus

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Temsirolimus
Temsirolimus.svg
Clinical data
Trade names Torisel
Other namesCCI-779
AHFS/Drugs.com Monograph
MedlinePlus a607071
License data
Pregnancy
category
  • AU:D
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 17.3 hours (temsirolimus); 54.6 hours (sirolimus) [2]
Excretion Urine (4.6%), faeces (78%) [2]
Identifiers
  • (1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-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-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.211.882 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C56H87NO16
Molar mass 1030.303 g·mol−1
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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.

Contents

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; [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

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. [12]

Adverse reactions

The toxicity profile is based on what was found in the phase III trial. [13]

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

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. [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

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. [13] [16]

See also

Related Research Articles

<span class="mw-page-title-main">Sirolimus</span> Pharmaceutical drug

Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin (mTOR) kinase inhibitor that reduces the sensitivity of T cells and B cells to interleukin-2 (IL-2), inhibiting their activity.

<span class="mw-page-title-main">Everolimus</span> Chemical compound

Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Sorafenib</span> Chemical compound

Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

<span class="mw-page-title-main">Sunitinib</span> Cancer medication

Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.

<span class="mw-page-title-main">Von Hippel–Lindau tumor suppressor</span> Mammalian protein found in Homo sapiens

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<span class="mw-page-title-main">Epithelioid sarcoma</span> Medical condition

Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first definitively characterized by F.M. Enzinger in 1970. It commonly presents itself in the distal limbs of young adults as a small, soft mass or a cluster of bumps. A proximal version has also been described, frequently occurring in the upper extremities. Less commonly, cases are reported in the pelvis, vulva, penis, and spine.

<span class="mw-page-title-main">Lenvatinib</span> Chemical compound

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

<span class="mw-page-title-main">Tivozanib</span> Medication

Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of advanced renal cell carcinoma. It is an oral VEGF receptor tyrosine kinase inhibitor.

<span class="mw-page-title-main">Dactolisib</span> Chemical compound

Dactolisib is an imidazoquinoline derivative acting as a PI3K inhibitor. It also inhibits mTOR. It is being investigated as a possible cancer treatment.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.

<span class="mw-page-title-main">Papillary renal cell carcinoma</span> Medical condition

Papillary renal cell carcinoma (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all kidney neoplasms. Based on its morphological features, PRCC can be classified into two main subtypes, which are type 1 (basophilic) and type 2 (eosinophilic).

<span class="mw-page-title-main">Belzutifan</span> Chemical compound

Belzutifan, sold under the brand name Welireg, is an anti-cancer medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma. It is taken by mouth. Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.

<span class="mw-page-title-main">HL156A</span> Chemical compound

HL156A is a derivative of metformin and a potent oxidative phosphorylation inhibitor and AMP-activated protein kinase activating biguanide. Certain types of cancer cells requires oxidative phosphorylation to survive. By targeting it, HL156A might help in improving anticancer therapy. It is more potent than acadesine or metformin at activating AMP-activated protein kinase. It is synthesized by Hanall Biopharma.

References

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  2. 1 2 Temsirolimus Drug Monograph. Cancer Care Ontario. June 2014. p. 2.
  3. "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.
  4. Hastings, Kenneth. "Pharmacology Review, Application Number 22-088" (PDF). FDA. Retrieved 7 March 2015.
  5. "Temsirolimus Monograph for Professionals". Drugs.com. Retrieved 7 March 2015.
  6. 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.
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  16. 1 2 Temsirolimus Drug Monograph. Cancer Care Ontario. June 2014. p. 4.