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by Dorothy Williams | Mar 19 2012

Introduction: The VEGFR pathway

The VEGF pathway is the mechanism by which a mammalian system regulates the growth of vascular structures, such as blood vessels and lymphatic vessels. There exists three iso-forms of VEGFR spread across the cellular membrane of mostly endothelial cells, with a head in the extracellular medium and a tail in the cytosole[1]. Ligand activity dimerizes the receptor and causes conformational changes to be transferred down the protein structure into the tail section where tyrosine kinase binding domains are revealed. There exists seven know ligands for the VEGF receptors known simple as VEGF-A, B, C, D, E, F or G [2;3]. VEGF-A binds only to VEGFR 1 or 2 and it is reported that this is predominately regulates the formation and maintenance of the vascular system. VEGFR1 doesn’t appear to have a direct function of cellular response but has been suggested that it regulates VEGFR2 activity [4;5]. VEGFR3 is less well known and only discovered recently, it appears to bind only to VEGF-C or D regulating the lymphatic system. Inhibition of the VEGFR focuses mainly on the isoforms VEGFR2 since this receptor is 90% responsible for all activity in this pathway [6]. Pazopanib is a small molecule that inhibits all VEGFR isoforms and has demonstrated anti-tumor activity [7].

Pazopanib: Properties and availability

The Pazopanib VEGFR inhibitor is under development by the Pharmaceutical Company GlaxoSmithKline and is assigned the trade names of Armala and Votrient. Its original research code name was GW786034B and it is supplied as the hydrochloride salt. Pazopanib is multi-kinase inhibitor with specificity towards VEGFR 1,2&3 isoforms, in addition Pazopanib has activity against cKIT, PDGFR (α&β) and cFMS. Pazopanib IC50’s for inhibition of the 1,2&3 VEGF isoforms are in the 30±17 nM range, where as the other activities have IC50 ten fold higher[8]. Pazopanib structure consists of three main sections; a benzene sulphonamide and a dimethyl indazol linked together by pyrimidine giving Pazopanib its unique activity. The Pazopanib solubility is poor in both aqueous and alcoholic solutions, surprisingly Pazopanib is soluble to DMSO only up to 8.3 mg/ml, presenting significant problems in preparation of cell culture buffers. Maximum aqueous concentrations are estimated to be in the 10-20 µM range and only the addition of protein to the buffered preparation will keep this compound in solution.Pazopanib stability of the solid material is estimated at 2 years if kept at -20°C, however, caution should taken in the freezing of stock solutions since Pazopanib can be difficult to get back in solution on defrosting. To buy Pazopanib is relatively easy and many Pazopanib suppliers exist for research material. The Pazopanib price of 25 mg vial range between $62 and $395 although purity remains consistent between suppliers.

Pazopanib: Preclinical Investigation

Initial investigations in multiple myeloma for activity of Pazopanib demonstrated a reduction of angiogenesis and an increase apoptotic cell death in both the tumor and the endothelial cells [9]. In renal cell carcinoma and other solid tumors Pazopanib has demonstrated apoptotic effects, linked to the key role VEGF plays in these diseases. In hematological conditions VEGF also is instrumental in the uncontrolled cell survival, Pazopanib proved to equally effective in reducing tumor mass and inducing cell death. Pharmacokinetic (PK) and pharmacodynamic (PD) parameters for tyrosine kinase inhibitors like Pazopanib have been recognized as indicating eventual human sensitivity and efficacy of these drugs. In murine model systems the PK and PD parameters were determined. For an initial phase 1 screening PK and PD parameters were measured and demonstrating direct correlation to the murine model [10-12]. The extensive preclinical testing demonstrate a clear potential use for this molecule in renal cell carcinoma and phase I clinical trials were fast tracked by FDA approval [13-21]. In 2009 Pazopanib was approved for first line use in treatment of renal cell carcinoma barely 3 years since its first introduction into the clinical testing phase.

Pazopanib: Clinical Status

In addition to extensive phase II and Phase III in all forms of renal cell carcinomaPazopanib clinical trials have been initiated in tumors where VEGFR plays a pivotal role. In conditions such as breast cancer [22;23], prostate cancer [24;25], liver cancer [26], thyroid cancer, soft cell sarcoma [27] and NSCLC [28-30]VEGFR has been observed to be elevated, promoting cell survival.


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