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TEMSIROLIMUS

by Selleckchem | May 27 2012

TEMSIROLIMUS: mTOR INHIBITOR
mTOR protein kinase enzymes are the proteins that belongs to PI3-K (phosphatidylinositol 3-kinase) which is associated with the family of kinase proteins and are responsible for regulation of cell survival, growth, proliferation, transcriptional activities, cell migration and protein synthesis. Just because of the effect of these inhibitors on the above mentioned phenomenon, the targeting of these enzymes to treat various types of cancers is now an attractive approach. In past Rapamycin was known to be the most valuable inhibiting drug that belongs to the class of mTOR inhibitors but now days another member of this family named Temsirolimus mTOR inhibitor is more famous than that one.
Temsirolimus Torisel is one of those few inhibitors which are now on waiting list for an approval from FDA for the treatment of renal cell carcinoma or RCC. Wyeth Pharmaceuticals are the manufacturers of Temsirolimus 162635-04-3 and it has intravenous administration to the patients. Temsirolimus is also known as CCI-779. One can purchase Temsirolimus by paying Temsirolimus price to the suppliers as they are supply it for research and laboratory purposes. Temsirolimus supplier sells this drug under the trade name Torisel. Temsirolimus structure describes it as a derivative of a drug named Sirolimus. It is insoluble in water while the Temsirolimus solubility is around 200 mg/mL in DMSO and ethanol. Temsirolimus is stable at -20ºC even for two years. Its cost varies according to rate of purity of salt. Temsirolimus price is around $100 for a 200 mg vial.

TEMSIROLIMUS: THERAPEUTIC USES AND MODE OF ACTION
Temsirolimus CCI-779 has the same mode of action as different other mTOR inhibitor molecules [1]. In past, Temsirolimus was used for the treatment of multiple kinds of tumors especially Pompe disease in the recent years. Temsirolimus function is actually to make the cells of the patients sensitive to SCLC or Cisplatin therapy as those cells were resistant to Cisplatin small cell lung cancer [4]. After assessing it completely and getting proper evidences its anti-angiogenic effects in in-vitro and in-vivo both models, Temsirolimus has been used as a good and remarkable anti-angiogenic agent.
Temsirolimus has proved itself in xenograft models of rhabdomyosarcoma as an anti-angeogenic drug [6]. Recently, Temsirolimus drug has shown itself as a very effective agent against mammary tumors preclinical models or PyMT [8] while it was also been used against breast cancer in combination with other drugs [7]. The Temsirolimus safety profile was studied in patients of metastasis [9] and advanced renal cell carcinoma [10] and this information was used in the clinical trials phase I and phase II in the combination of Interferon-alpha.

TEMSIROLIMUS: CLINICAL TRIALS
Temsirolimus was applied in the clinical trials phase I as a combination therapy for the treatment of advanced forms of tumors [14] after the assessment of Temsirolimus pharmacokinetic properties in phase I trials [13]. Different other combinations were used as well in clinical trials phase I against the advance breast carcinoma and gynecologic malignancies, and it was also seen that Temsirolimus alone is very effective against breast cancer patients under clinical trials phase II [16]. It has also promised very good results alone in case of solid form of tumors [17] or in combination with some other drugs [18] in clinical trials phase I. it has also got approval against the pediatric patients [19]. Temsirolimus has also exhibited remarkable results in phase II clinical trials of NSCLC [20].
In Temsirolimus clinical trials, most remarkable were those related to mantle cell lymphoma. For those clinical trials Temsirolimus was used in a very low dosage [21] in phase II or as a part of some combined therapy [22]. Tremendous results were obtained in those clinical trials that prompted the scientists to use Temsirolimus in phase III clinical trials against same disease where it has fulfilled the expected anticipations successfully [23]. Phase II clinical studies against ovarian cancer [24], endometrium malignancy [25], neuroendocrine cancer [27], soft tissue sarcoma [26], and the most important glioblastoma [28] were carried out as well, where it has shown promising results.

REFERENCES:
1. Rini, B.I.e.a., Temsirolimus, an Inhibitor of Mammalian Target of Rapamycin. Clin Cancer Res, 2008.
2. Dancey, J.E.e.a., Evaluating Temsirolimus Activity in Multiple Tumors: A Review of Clinical Trials. Seminars in Oncology, 2009.
3. Ashe, K.M.e.a., Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease. Molecular Genetics and Metabolism, 2010.
4. Wu, C.e.a., Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol. Cancer, 2005.
5. Del Bufalo, D.e.a., Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res., 2006.
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.
10. Bellmunt, J.e.a., Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol., 2008.
11. Grundbichler, M.e.a., Efficacy of Temsirolimus after Previous Treatment with Sunitinib, Sorafenib or Everolimus in Advanced Renal Cell Cancer. Oncology, 2011.
12. Motzer, R.J.e.a., Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma. Journal of Clinical Oncology, 2007.
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. Naing, A.e.a., Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer. Clinical Cancer Research, 2011.
15. 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.
16. 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.
17. MacKenzie, M.J.e.a., A phase I study of temsirolimus and metformin in advanced solid tumours. Investigational New Drugs, 2010.
18. Kollmannsberger, C.e.a., Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179). Ann Oncol., 2011.
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. 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.
25. 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.
26. Okuno, S.e.a., A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas. Cancer, 2011.
27. Duran, I.e.a., A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. British Journal of Cancer, 2006.
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.