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SUNITINIB: THE MULTI-TARGETED APPROACH

by Selleckchem | May 31 2012

MUTIKINASE INHIBITORS IN CHEMOTHERAPEUTICS:
Different types of metabolic systems that occur between varieties of cells are mediated through a class of enzymes called tyrosine kinases. Since these tyrosine kinases play important role in processes e.g. division, survival, multiplication, differentiation, growth and death of cell, their inhibition have been found very promising target. By doing any change in them the processes which they regulate can also be down regulated. This behaviour is being exploited as inhibitors of tyrosine kinases for chemotherapy. The inhibitors of tyrosine kinases block multiple kinases at the same time. The involvement of tyrosine kinases in the pathways which cause different cancers like it is involved in vascular endothelial growth factor pathway in case of breast cancer and many other types of cancer makes them interesting [1]. Different types of carcinomas are being successfully treated by using inhibitors of tyrosine kinase [2]. Tumors of stromal gastrointestinal are also being treated by administering inhibitors that can block various tyrosine kinases [3].These inhibitors are also being used for the treatment of ALL (Acute Lymphoblastic Leukaemia) [4].

SUNITINIB:
Sunitinib supplier can provide Sunitinib to anyone who wants to buy Sunitinib under the trade name of either Sunitinib Sutent or Sunitinib malate. It inhibits multiple tyrosine kinases and has been seen very efficient therapeutic agent. Sunitinib structure shows Sunitinib IC50 is variable for different inhibitors for example carboxamide, VEGFR1, PDGFR and c-KIT have 2nM, 17nM, 2-3nM and 4 to 8 respectively. The economical price of Sunitinib makes it suitable for researchers to use it for experiments. Sunitinib price for a vial of 1g is only $80. 40 mg/ml of dimethyl sulfoxide (DMSO) is suitable for Sunitinib solubility since it partially soluble in ethanol and water. At -20oC Sunitinib is stable for almost 2 years. A number of data is available which shows that Sunitinib acts as an inhibitor of multiple tyrosine kinases and have been shown to have both anti-proliferative and and anticancer activity [5]. Clinical trials on humans have been conduct to assess the pharmacokinetic properties and safety of Sunitinib [6]. The results supported the fact that it can be used as therapeutic agent for treating cancer [7-8]. Sunitinib VEGFR inhibitors as well as Sunitinib PDGFR inhibitor both have been shown to have strong anti-angiogenic effect [9]. Positive results were seen on small cancer cells of lung or NSCLC by using tyrosine kinase inhibitor FLT3 [10]. FLT3 TKI has also been administered as anti-VEGF therapy and for treatment of ALL conducted in clinical trial sphase III [11-13]. Sunitinib c-kit inhibitor which is also a TKI has been found very effective for the treatment of renal cancer [14]. In humans different forms of metastasizing tumours of blood are being treated by using it [15].

SUNITIB: CLINICAL STATUS
Fruitful results have been seen of the Sunitinib Clinical trial Phase I of Clinical trials consisted of the study of mechanism of Sunitinib [16] and it gave plentiful knowledge about its mechanism of action. Phase II clinical trials consisted of evaluation of its effect in patients suffering from late stages of lung cancer in NSCLC [17-18]. In clinical trials phase II it has shown positive results in the treatment of colorectal carcinoma [19]. Phase II clinical trials consisting of patients suffering from B-cell lymphoma have also shown promising results after Sunitinib administration [20-21]. Clinical trials phase II comprises of patients suffering from ovarian carcinoma were also treated with Sunitinib having multiple tyrosine kinase activity [22]. In phase I and II clinical trials Sunitinib was co-administrated with both Docetaxel and Prednisone in patients having prostate cancer and gave the positive results [23]. Safety and efficiency evaluation of Sunitinib in gastrointestinal stromal tumours are well reported which made it a strong candidate to enter the clinical trials Phase III for the treatment of patients suffering from GISTs [24-25]. Patients having renal cell cancer have also been treated by using Sunitinib [26]. Phase III ofclinical trials consisted of individuals having cancer of pancreatic endocrine were administered with Sunitinib and very promising and outstanding results were obtained [27].

REFERENCES:
1. Gasparini, G.e.a., Prognostic Value of Vascular Endothelial Growth Factor in Breast Cancer. The Oncologist, 2000
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.
4. Illmer, T.e.a., FLT3 Kinase Inhibitors in the Management of Acute Myeloid Leukemia. Clinical Lymphoma, Myeloma & Leukemia, 2007.
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.
8. Hartmann, J.T.a.K., L., Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol., 2008.
9. Roskoski, R.e.a., Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochemical and Biophysical Research Communications, 2007.
10. Socinski, M.e.a., The Current Status and Evolving Role of Sunitinib in Non-small Cell Lung Cancer. Novel Agents in the Treatment of Lung Cancer, 2008.
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.