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TEMSIROLIMUS

by Selleckchem | Mar 20 2012

TEMSIROLIMUS AND mTOR INHIBITORS:

mTOR protein kinases belonging to phosphatidylinositol 3-kinase (PI3-K) which is related to the family of kinase proteins are responsible to regulate cell growth, survival, proliferation, protein synthesis, cell’s transcriptional activities and cell migration. Because of their influence on all of the above mentioned processes, targeting many of these enzymes for the treatment of various diseases is now a very valuable approach. Previously Rapamycin was found to be the most famous inhibitor belonging to category mTOR but these days another member of same family named as Temsirolimus mTOR inhibitor is also getting popularity.

Temsirolimus is one of such few drugs which are waiting an approval from FDA to treat RCC or renal cell carcinoma. Temsirolimus is designed by Wyeth Pharmaceuticals and actually intravenously administrable. Temsirolimus is also named as CCI-779. Any one can buy Temsirolimus from Temsirolimus suppliers also buy the trade name Torisel as they supply it for laboratory purposes as well.Temsirolimus structure reveals that it is a derivative of the drug Sirolimus.Temsirolimus solubility in ethanol and DMSO is around 200 mg/ml while it is poorly soluble in water. Temsirolimus stability is found to be around 2 years when stored at -20ºC. Temsirolimus cost varies considerably according to the rate of purity of salt while the Temsirolimus price is almost $100 for a vial containing 20 mg.

THERAPEUTIC USES AND MECHANISM OF TEMSIROLIMUS:

Temsirolimus mechanism is almost same like various other mTOR inhibitors [1]. Previously Temsirolimus was found to be use for treating various multiple types of tumors while especially for Pompe disease in recent years. Function of Temsirolimus is actually to sensitize the cells of those patients to Cisplatin therapy which are previously resistant to Cisplatin small cell lung cancer or (SCLC) [4]. After the complete assessment and getting evidences for Temsirolimus’s anti-angiogenic effects in both in vivo and in vitro models it has been used as a very valuable anti-angiogenic agent. Temsirolimus has also proved itself as an anti-angeogenic agent in rhabdomyosarcoma xenograft models as well [6]. Recently Temsirolimus compound has shown itself very effective in mammary carcinoma PyMT or preclinical models [8] while it has also been used for studying breast carcinoma combining with some other drugs [7]. Safety profile of Temsirolimus was analyzed in patients suffering from advanced form of renal cell cancer [10] and metastasis [9] and this information was utilized for treatment of RCC by combining with different other drugs [11]. It has also been used in clinical trials of phase I and II in combination with Interferona [12].

TEMSIROLIMUS: PATIENTS’ LEVEL

Temsirolimus was used for the clinical trials of phase I like a combination therapy for treating advanced tumors [14] after studying the pharmacokinetics of Temsirolimus in phase I [13]. Various other combinations were also used in trials of phase I against gynecologic malignancies and advance breast carcinoma and it was found alone very effective in case of clinical trials phase II of breast carcinoma [16]. It also promised good results against solid tumors alone [17] or in combination with others [18] in trials of phase I. Temsirolimus has also been approved against pediatric patients [19]. Temsirolimus also worked remarkably in NSCLC clinical trials of phase II [20].

Among Temsirolimus clinical trials, the most successful were in case of mantle cell lymphoma. In those trials Temsirolimus was analyzed in a low dosage [21] for phase II or like a part of combine therapy [22]. Temsirolimus gave tremendous results in those trials which prompted the scientist to use it in phase III trials of the same disease where it fulfilled the anticipations very successfully [23]. Some phase II clinical trials were also carried out in ovarian cancer [24], sarcoma of soft tissue [26], malignancy of endometrium [25], neuroendocrine cancer [27] and toughest of all above mentioned is patients of GBM [28], where Temsirolimus has made good records of success.

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.