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TEMSIROLIMUS- AN mTOR INHIBITOR

by Selleckchem | Apr 18 2012

TEMSIROLIMUS
Different types of protein kinases are there that function in the cell signaling process for the activation or inhibition of cellular processes like gene expression for division, growth, differentiation etc. mTOR protein kinases are one of such cell cycle regulatory proteins. They belong to PI3-K (phosphatidylinositol 3-kinase) related kinase family of proteins. mTOR proteins are involved in the regulation of proliferation of cells, growth, cell survival and migration, synthesis of proteins and activities related to transcription in the cell. As they influence a lot of cell cycle regulating pathways, any disturbance in these or the proteins which they influence, may cause cancer in the tissue. Therefore these mTOR proteins are the best targets for anti-cancer drugs. Rapamycin is one of these mTOR inhibitors which are well known. Temsirolimus mTOR inhibitor, another important inhibitor is being researched nowadays.

PROPERTIES OF TEMSIROLIMUS
Temsirolimus also named as CCI-779, has been developed by Wyeth Pharmaceutical Company and has got the approval of FDA for (RCC) renal cell carcinoma treatment. Temsirolimus CCI-779 is administered intravenously and is available as the trade name of Torisel. Researchers or doctors can buy Temsirolimus for their purposes. Temsirolimus structure resembles Sirolimus and Temsirolimus solubility is can be upto 200 mg/ml in ethanol as well as DMSO and no solubility in water. Temsirolimus stability can be obtained upto two years if preserved at -20 oC. Temsirolimus price of a 20 mg vial is approximately $100.

MECHANISM OF ACTION OF TEMSIROLIMUS
Temsirolimus has been used against multiple types of tumors [1]. It acts like other mTOR inhibitors [2]. Recently the drug has been used against Pompe disease [3]. The drug has also been observed to re-sensitize the SCLC cells that developed resistance against Cisplatin therapy [4]. Temsirolimus also showed ant-angiogenic capability in in vivo and in vitro models [5] and in xenografts from rhabdomyosarcoma too [6]. For studies in in vivo conditions Temsirolimus has been used in combinatorial therapy with other drugs against breast cancer [7]. It was also studied for mammary carcinoma in PyMT models [8]. Safety profile of Temsirolimus was studied in renal cell carcinoma in advanced and metastatic state [9-10] and was used in combination with some other drugs for the treating RCC [11] e.g., IFNin clinical trial phase I/II [12].

TEMSIROLIMUS CLINICAL TRIALS
Pharmacokinetics of Temsirolimus were studied as single agent in clinical trial phase I [13] and was used successfully against breast cancer in phase II [14] or in a combinatorial therapy for advanced tumors [15] e.g., advanced gynecologic and breast malignancies [16]. In case of solid tumors it was studied as a single agent in phase I clinical trial and gave efficacious results [17]. It was also used for the same purpose in combination with other drugs [18] and its use was approved against pediatric problems too [19]. Temsirolimus clinical trials showed promising results in case of NSCLC [20].
For mantle cell lymphoma Temsirolimus showed remarkable results in clinical trial phase II and it is considered the biggest success in case of Temsirolimus as it was studied in low dose [21] and in combinatorial therapy [22]. These results encouraged the scientists to study this drug in clinical trial phase III which also went successful [23]. Moreover successful clinical trials in phase II were done on some other cancers like neuroendocrine carcinoma [24], ovarian malignancy [25], soft tissue sarcoma [26], endometrial malignancy [27], and the most difficult of all to treat in patients of GBM (Glioblastoma Multifome) [28]. More research on the drug is undergoing in order to unveil its other roles too.

REFERENCES
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4. Wu, C.e.a., Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol. Cancer, 2005.
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6. Wan, X.e.a., CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia, 2006.
7. Sadler, T.M.e.a., Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus. Endocr Relat Cancer, 2006
8. Wang, X.e.a., Multi-Modal Biomarker Investigation on Efficacy and Mechanism of Action for the mTOR inhibitor, Temsirolimus, in a Preclinical Mammary Carcinoma Oncomouse (PyMT) Model: A Translational Medicine Study in Support for Early Clinical Development. Journal of Pharmacology and Experimental Therapeutics, 2011.
9. Lamm, W.e.a., Safety and efficacy of temsirolimus in heavily pretreated patients with metastatic renal cell carcinoma. Acta Oncologica, 2011.
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11. Grundbichler, M.e.a., Efficacy of Temsirolimus after Previous Treatment with Sunitinib, Sorafenib or Everolimus in Advanced Renal Cell Cancer. Oncology, 2011.
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13. Hidalgo, M.e.a., A Phase I and Pharmacokinetic Study of Temsirolimus (CCI-779) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients with Advanced Cancer. Clin Cancer Res, 2006.
14. Chan, S.e.a., Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer. Journal of Clinical Oncology, 2005.
15. Naing, A.e.a., Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer. Clinical Cancer Research, 2011.
16. Moroney, J.W., A Phase I Trial of Liposomal Doxorubicin, Bevacizumab and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies. Clinical Cancer Research, 2011.
17. MacKenzie, M.J.e.a., A phase I study of temsirolimus and metformin in advanced solid tumours. Investigational New Drugs, 2010.
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19. Spunt, S.L.e.a., Phase I Study of Temsirolimus in Pediatric Patients With Recurrent/Refractory Solid Tumors. Journal of Clinical Oncology, 2011.
20. Pandya, K.e.a., A Randomized, Phase II Trial of Two Dose Levels of Temsirolimus (CCI-779) in Patients with Extensive-Stage Small-Cell Lung Cancer Who Have Responding or Stable Disease after Induction Chemotherapy: A Trial of the Eastern Cooperative Oncology Group (E1500). Journal of Thoracic Oncology, 2007.
21. Ansell, S.M.e.a., Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma. Cancer, 2008.
22. Ansell, S.M.e.a., Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. The Lancet Oncology, 2011.
23. Hess, G.e.a., Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma. Journal of Clinical Oncology, 2009.
24. Duran, I.e.a., A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. British Journal of Cancer, 2006.
25. Behbakht, K.e.a., Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: A Gynecologic Oncology Group study. Gynecologic Oncology, 2011.
26. Okuno, S.e.a., A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas. Cancer, 2011.
27. Oza, A.M.e.a., Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group. Journal of Clinical Oncology, 2011.
28. Galanis, E.e.a., Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. Journal of Clinical Oncology, 2005.