PAZOPANIB – A NOVEL VEGFR INHIBITOR FOR CANCER TREATMENT

by Selleckchem | Mar 27 2012

PAZOPANIB INTRODUCTION:
Pazopanib is a product of GlaxoSmithKilne (GSK) pharmaceutical company and is traded under the name of Votrient, it is an anti-angiogenic chemical compound. Pazopanib VEGFR-PDGFR inhibitor which acts on multiple VEGFR (R1, R2 and R3) and it is also a potent inhibitor of PDGFR’s α and β subtypes and RTK c-kit receptor is also found to be inhibited by Pazopanib. In recent years great potency of this compound has been reported against different tumors and these findings brought fame to this molecule. It is amongst few VEGFR inhibitors which are approved for clinical usage [1]. The structure of Pazopanib contains a sulfonamide group. The Pazopanib price for a vial of 25mg is about $100 but it variability is found from one Pazopanib supplier to other. If someone wants to purchase Pazopanib one can buy Pazopanib by trade name Votrient or GW786034. This compound is soluble in the DMSO and it is stable for atleast two years when stored at -20oC. IC50 for its effective response is 10nM, 30nM and 47 nM for VEGFR1, R2 and R3 respectively. And IC50 for PDGFR-beta FGF R1, c-fims and c-Kit is 84nM, 140nM, 74nM, 146 nM and 140nM respectively.

PAZOPANIB IN VIVO AND IN VITRO TRIALS:
Not only the discovery of Pazopanib but also the initial results of different research groups produced a good buzz to take it in clinical trials [2]. A manageable, safe and also tolerate able toxicity profile along with good pharmacokinetics favored its uses at clinical level experimentation [3]. Pazopanib’s steady-state concentration based on the preclinical findings corroborated its pharmacodynamic actions and antitumor actions in clinical trials phase-I [4]. Pazopanib in its action found to affect endothelial cells in MM (multiple myeloma) and tumor cells as well during in vitro studies [5]. In mice models, Pazopanib was able to check choroidal neovascularization (CNV) [6]. Non invasive assessment was also done by the help of molecular imaging technique [7], the study was successful and can be utilized in advance studies. Recently, in breast cancer treatment it was found that Pazopanib acts on B-Raf and same results were also reported for the cell lines of melanoma [8]. In case of small cell lung cancer (NSCLC) it was effective when used with Lapatinib [9]. Mice model having aggressive pediatric solid tumors were treated with Pazopanib and Topotecan and this combination was efficient [10].

SUCCESSFUL CLINICAL RESULTS OF PAZOPANIB:
Pazopanib is currently undergoing clinical trials pahse II, based on bone sarcoma and tissue sarcoma [11]. The results of the phase II trials are promising for patients of renal cell carcinoma (RCC) [12]. However phase III Pazopanib treatment results are encouraging for locally or metastatic advanced renal cell carcinoma [13]. This compound is found as effective in monotherapy as well as with combination to other compounds such as Lapatinib, these combinations promote its uses for the combination therapy [14]. In patients with prostate cancer are also treated well by Pazopanib therapy during phase II studies [15]. Cyclophosphamide and Pazopanib combination therapy for the pre-treated recurrent ovarian cancer patients is also enrolled for phase I/II studies and resulted in the synergistic actions [16]. In addition to these studies, during phase II Pazopanib was also applied against metastatic or recurrent nasopharyngeal carcinoma patients of Asia [17].

REFERENCES:
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2. Harris, P.e.a., Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor. J. Med. Chem., 2008.
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4. Kumar, R.e.a., Mol Cancer Therap. 2007.
5. Podar, K.e.a., The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. PNAS, 2006.
6. Takahashi, K.e.a., The Multi-targeted Kinase Inhibitor Pazopanib Causes Suppression and Regression of Choroidal Neovascularization. Arch Ophthalmol., 2009.
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9. Olaussen, K.e.a., Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines. Oncogene, 2009.
10. Kumar, S.e.a., Metronomic Oral Topotecan with Pazopanib Is an Active Antiangiogenic Regimen in Mouse Models of Aggressive Pediatric Solid Tumor. Clin Cancer Res, 2011.
11. Sleijfer, S.e.a., Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients with Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). Journal of Clinical Oncology, 2009.
12. Hutson, T.e.a., Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology, 2010.
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17. Lim, W.e.a., Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma. Clin Cancer Res, 2011.