PAZOPANIB: INTRODUCTION

by Selleckchem | Jul 19 2012

PAZOPANIB: INTRODUCTION
One of the very important anti-tumor drugs Pazopanib VEGFR inhibitor also known as Pazopanib Votrient is being produced by the very popular pharmaceutical company which is GlaxoSmithKline. It is selling this drug with commercial name of Votrient. Pazopanib inhibits the angiogenesis by blocking VEGF R1, R2 and R3 with their β subtypes and also inhibits c-kit RTKs as well as PDGFR-a. Though Pazopanib is tiny molecule yet it gains popularity due to its extensive potential on various kinds of malignancies. Pazopanib VEGFR-PDGFR inhibitor has now been approved to enter the clinical trials [1]. It was revealed by the Pazopanib structure that it contained a sulfonamide group. It is marketed in 25mg of packaging with Pazopanib price of approximately $100 as Votrient or GW786034 and anyone can purchase Pazopanib for research or experimental purposes from supplier Pazopanib. Prices are being varied from supplier to supplier. Pazopanib solubility revealed it is best soluble in DMSO while it is absolutely insoluble in water and ethanol. Storing at -20oC shows stability for approximately 2 years. The studies revealed that Pazopanib IC50 value for VEGF-R1 is 10nM, for VEGF-R2 is 30nM and for VEGF-R3 is 47nM. Pazopanib IC50 values for few related kinases for example PDFGR-beta is 82nM, c-fms is 146nM, c-kit is 74nM and FGFR1 is 140nM.

IN VITRO AND IN VIVO CLINICAL TRIALS OF PAZOPANIB
For the production and its studies in clinical trials were supported by the Pazopanib Votrient initial screening and discovery [2]. The urge to carry out its clinical studies and its market value was increased by its characteristics properties such as tolerability, safety, adaptability and outstanding pharmacokinetics profile [3]. The equal concentration of Pazopanib revealed by pre-clinical trials has contributed to carry clinical trials phase I consisting of its study as anti-neoplastic drug and pharmacodynamics properties [4]. Pazopanib GW786034 targeted endothelial and also tumor cells when in vitro cell culture studies were conducted [5]. When administered in mince suffering from CNV or choroidal neovascularization it showed specific and outstanding targeting [6]. Molecular imaging method was employed to assess Pazopanib by non-invasive technique [7] and it can be further used. Pazopanib c-kit inhibitor was shown to target the melanoma cell lines and breast cancer cells expressing protein called B-Raf in a recent study performed [8]. It showed promising results in the treatment of NSCLC when co-administered with Lapatinib [9].Pediatric solid tumors in mice were treated by co-administration of Pazopanib with Topotecan [10].

CLINICAL ACHIEVEMENT OF PAZOPANIB
Bone and tissue sarcoma were administered with Pazopanib GW786034 in phase III clinical trials [11]. Phase II clinical trials consisted of patients suffering from kidney cancer were administered with it and showed fruitful results [12]. Outstanding results were shown by Pazopanib when it was administered in patients of advanced stages of kidney cancer of phase II trials [13].Although it is very effective when administered alone but its co-administration with Lapatinib has increased its value among the combinational therapies [14]. Brilliant efficiency was shown by Pazopanib when administered in patients suffering from prostate cancer that are castration-sensitive in clinical levels of phase II [15]. When co-administered with Cyclophosphamide in patients of pre-treated or relapsed patients of ovarian cancer it showed fruitful results in II and I clinical trials [16]. The study of patients having metastasized or relapsed nasopharyngeal cancer and belonging from Asia was conducted in Pazopanib clinical trial of phase II [17].

REFERENCES:
1. Bukowski, R.e.a., Pazopanib. Nature Reviews Drug Discovery, 2010.
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.
3. Sonpavde, S.a.H., TE, Pazopanib: A novel multitargeted tyrosine kinase inhibitor. Current Oncology Reports, 2007.
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.
7. Blankenberg, F.e.a., Noninvasive Assessment of Tumor VEGF Receptors in Response to Treatment with Pazopanib: A Molecular Imaging Study. Transl Oncol., 2010.
8. Gril, B.e.a., The B-Raf Status of Tumor Cells May Be a Significant Determinant of Both Antitumor and Anti-Angiogenic Effects of Pazopanib in Xenograft Tumor Models. PLoS ONE, 2011.
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.
13. Sternberg, C.e.a., Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. Journal of Clinical Oncology, 2010.
14. Sloan, B.a.S., NS, Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs, 2008.
15. Ward, J.e.a., A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study. Prostate Cancer and Prostatic Diseases, 2011.
16. Eichbaum, M.e.a., The PACOVAR-trial: A phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer. BMC Cancer, 2011.
17. Lim, W.e.a., Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma. Clin Cancer Res, 2011.

Cat.No.	Product Name	Information
S1231	Topotecan HCl	Topotecan HCl is a topoisomerase I inhibitor for MCF-7 Luc cells and DU-145 Luc cells with IC50 of 13 nM and 2 nM in cell-free assays, respectively. Topotecan HCl induces autophagy and apoptosis.
S1271	Acarbose	Acarbose(BAY g 5421,Prandase, Precose, Glucobay, Bay-g 5421) is an inhibitor of intestinal alpha-glucosidase, used to treat type 2 diabetes mellitus.
S1305	Mercaptopurine (6-MP)	Mercaptopurine(6-MP) is a widely used antileukemic agent and immunosuppressive drug that inhibits de novo purine synthesis through incorporation of thiopurine methyltransferase metabolites into DNA and RNA.