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SUNITINIB: THE MULTI-TARGETED APPROACH

by Selleckchem | May 23 2012

MUTIKINASE INHIBITORS IN CHEMOTHERAPEUTICS:
Tyrosine kinases are the enzymes which act as mediators between different cells to facilitate variety of metabolic processes in the cells. The inhibition of these enzymes is found to be a very attractive target due to their prime role in various important processes in the cells for instance cellular growth, survival, proliferation, apoptosis and differentiation. Any type of modulation of these enzymes can cause the downstream regulation of the pathways controlled by them. This is why inhibitors to tyrosine kinases are getting very famous as chemotherapeutic agents. Many tyrosine kinase inhibitors are multikinase inhibitors as they can inhibit more than one type of tyrosine kinase enzymes. VEGF pathway involvement in breast carcinoma and some other tyrosine kinases in other cancers made these enzymes a popular interest [1]. Tyrosine kinase inhibitors are used successfully against solid form tumors [2] and various multi tyrosine kinase inhibitors are used for treating gastrointestinal stromal tumors [3]. Tyrosine kinase inhibitors are also employed for the treatment against acute form of lymphoblastic leukemia [4].

SUNITINIB:
One can buy Sunitinib from Sunitinib supplier by the name Sunitinib malate or Sunitinib Sutent. This multi tyrosine kinase inhibitor is found to be increasingly employed to start up its therapeutic potential. Sunitinib structure showed this inhibitor to be Sunitinib IC50 and carboxamide is 9, 2 and for VEGF-R1 inhibitor is 17 nM, 2 and 3, and 8 and 4 for respectively PDGF-R and c-KIT. Cost for Sunitinib is very reasonable and researchers can buy it easily for experimental purposes. Sunitinib price is just $80 for 1 gm vial. Sunitinib solubility is 40 mg/ml in DMSO while it is poorly soluble in water and ethanol. Sunitinib stability is found to be near 2 years when stored at -20oC. An abundance of data supports the role of Sunitinib as a multi tyrosine kinase inhibitor having anti-tumor and anti-angiogenic potential [5]. Safety profile and pharmacokinetic properties of Sunitinib were analyzed in humans [6] and it favored the successful use of Sunitinib Kit kinase inhibitor [7] in patients of cancer [8]. Sunitinib VEGFR inhibitor and the Sunitinib PDGFR inhibitor has found to be having potential angiogenic capability [9]. Strong promising results were obtained by the using FLT3 kinase inhibitor in case of NSCLC or small cell lung cancer [10]. FLT3 kinase inhibitor has been used in clinical trials of phase III for anti-VEGF therapy [11] and also as a FLT3 TKI [12] in acute form of lymphoblastic leukemia [13]. Tyrosine kinase inhibition by using Sunitinib c-kit inhibitor has found to be an efficient approach for treating renal carcinoma [14]. It has also been used against a variety of hematologic malignant forms of tumors in human [15].

SUNITIB: CLINICAL STATUS
Sunitinib Clinical trial has promised valuable results. From phase I clinical trial having Sunitinib mechanism [16], a great knowledge about the mode of action of Sunitinib is obtained. Scientists obtained very remarkable results in patients having advanced stage of lung carcinoma [18] under the phase II testing in NSCLC [17]. It also promised good results in case of phase II clinical studies of colorectal tumors [19]. Sunitinib has also been employed in patients of B-cell lymphoma patients under phase II [21]. The multi tyrosine kinase ability of Sunitinib is also being utilized for treating patients of phase II ovarian carcinoma [22]. Sunitinib employment combined with Docetaxel and Prednisone and gave promising results in patients of phase I and phase II trials of prostate cancer [23]. The well documentation of Sunitinib’s safety profile and efficiency for GISTs [24] further lead to the use of Sunitinib in GISTs patients under phase III clinical trials [25]. Sunitinib has also been used against patients of renal cell carcinoma [26]. It also promised good and remarkable results in tumors of pancreatic neuroendocrine phase III clinical trials [27].

REFERENCES:
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2. George, S., Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. Curr Oncol Rep., 2007.
3. Steeghs, N.e.a., Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments. Annals of Surgical Oncology, 2006.
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5. Christensen, J.G., A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Annals of Oncology, 2007.
6. Faivre, S.e.a., Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer. Journal of Clinical Oncology, 2006.
7. Abrams, T.J.e.a., SU11248 Inhibits KIT and Platelet-derived Growth Factor Receptor β in Preclinical Models of Human Small Cell Lung Cancer. Mol. Cancer Ther., 2003.
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11. Jain, R.K.e.a., Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology, 2006.
12. Stam, R.W.a.P., R., FLT3 Inhibitors as Therapeutic Agents in MLL Rearranged Acute Lymphoblastic Leukemia. New Agents for the Treatment of Acute Lymphoblastic Leukemia, 2011.
13. O'Farrell, A.e.a., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, 2003.
14. Ayllon, J.e.a., Long-Term Response and Postsurgical Complete Remissions After Treatment With Sunitinib Malate, an Oral Multitargeted Receptor Tyrosine Kinase Inhibitor, in Patients With Metastatic Renal Cell Carcinoma. Cancer Investigation, 2011.
15. Ikezoe, T.e.a., The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol. Cancer Ther., 2006.
16. Mena, C.e.a., Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib. Anti-Cancer Drugs, 2010.
17. Novello, S.e.a., Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. British Journal of Cancer, 2009.
18. Schneider, B.J.e.a., Phase II Trial of Sunitinib Maintenance Therapy After Platinum-Based Chemotherapy in Patients with Extensive-Stage Small Cell Lung Cancer. Journal of Thoracic Oncology, 2011.
19. Saltz, L.B.e.a., Phase II Trial of Sunitinib in Patients With Metastatic Colorectal Cancer After Failure of Standard Therapy. Journal of Clinical Oncology, 2007.
20. Buckstein, R.e.a., Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group. Leukemia & Lymphoma, 2011.
21. Burstein, H.J.e.a., Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane. Journal of Clinical Oncology, 2008.
22. al, B.J.J.e., A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Annals of Oncology, 2011.
23. Zurita, A.J.e.a., Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Annals of Oncology, 2011.
24. Demetri, G.D.e.a., Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. The Lancet, 2006.
25. Marx, J.e.a., Encouraging results for second-generation antiangiogenesis drugs. Science, 2005.
26. Eichelberg, C.e.a., Sequential Use of the Tyrosine Kinase Inhibitors Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma: A Retrospective Outcome Analysis. European Urology, 2008.
27. Raymond, R.e.a., Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med, 2011.