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SUNITINIB-AN RTK INHIBITOR

by Selleckchem | Jun 17 2012

MULTIKINASE INHIBITORS AND CHEMOTHERAPY
A variety of cell signalling pathways are there in the cellular systems of the body that govern different cellular processes in the cells. Tyrosine kinase pathways are one of these pathways that play role in growth, proliferation, survival and apoptosis etc. Overexpressed tyrosine kinases may hence lead to cancer and is amongst the major reasons in most of the cancer conditions. Inhibition of tyrosine kinases is hence being done by using different types of tyrosine kinase inhibitors. A single inhibitor may sometimes block multiple kinases in one time. The examples of cancers involving tyrosine kinase defects is breast cancer in which VEGF pathway is disturbed [1]. Various kinds of carcinomas involving such defects are being treated using these tyrosine kinase inhibitors [2] for example gastrointestinal stromal tumors [3] and Acute Lymphoblastic Leukaemia (ALL) [4].

SUNITINIB AND ITS PROPERTIES
Sunitinib is an example of the tyrosine kinase inhibitors that are actively being used and researched for the purpose of anti-cancer therapy. Sunitinib structure shows to have a small molecule which is soluble in DMSO upto 40 mg/ml. Sunitinib solubility is partial in water and ethanol. It can be preserved for upto 2 years if kept at -20 oC. The drug is available in the market by the name of Sunitinib malate or Sunitinib Sutent. One can buy Sunitinib in the form of a vial of 1g in 80$. Sunitinib IC50 for different activities is different e.g., for VEGFR1, carboxamide, c-Kit and PDGFR it is 17, 2, 4-8 and 2-3nM respectively.
A lot of research has been done on Sunitinib acting as anti-cancer and anti-proliferative agent by inhibiting multiple types of tyrosine kinases [5]. Pharmacokinetics and safety profile has been tested on humans in clinical trials [6] and it was suggested to be used as therapy for cancer [7-8]. Both Sunitinib VEGFR inhibitors and Sunitinib PDGFR inhibitor have very efficient effects on angiogenesis [9]. FLT3 Tyrosine Kinase inhibitor has shown quite positive effects in patients of small cell lung cancer and non-small cell lung cancer (NSCLC) [10]. It has also been given against VEGF in order to treat acute lymphoblastic leukemia (ALL) in phase III of clinical trial [11-13]. A similar Sunitinib c-kit inhibitor is very effective against renal cancer [14]. This drug is being used in humans to treat their blood metastasizing tumours [15].

SUNITIB IN CLINICS
Sunitinib clinical trial in phase I have been done in order to unveil the mechanism of action of the drug [16]. Clinical trials in phase II enabled scientists to study the effects of the drug in patients of non-small cell lung cancer (NSCLC) [17-18]. Positive results have also been seen in phase II clinical trial in the patients having colorectal carcinoma [19]. Sunitinib has also shown encouraging results in the patients of B-cell lymphoma when it was studied in phase II clinical trial [20-21]. The patients of ovarian cancer were also treated with Sunitinib in phase II clinical trial and remarkable results were seen [22]. In combinatorial therapy, Sunitinib was administered along with Prednisone and Docetaxel for treating prostate cancer patients and positive results were seen in this case too [23]. Safety profile and efficiency of the drug was evaluated in gastrointestinal stromal tumours and was found good and encouraging being studied in phase III clinical trial GISTs patients [24-25]. The drug is also being used in patients suffering from renal cell cancer [26]. Sunitinib has also shown efficacious results in patients of pancreatic endocrine cancer [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.