| Pazopanib is a novel orally available, small-molecule tyrosine kinase inhibitor of VEGF receptor (VEGFR) -1, -2, -3, PDGFR-α, PDGFR-β, and c-Kit with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively. Pazopanib is ATP-competitive inhibitor of human VEGFR2 tyrosine kinase with Ki of 24 nM. Pazopanib potently inhibits VEGF-induced phosphorylation of VEGFR2 in human umbilical vascular endothelial cells (HUVEC) with an IC50 of about 8 nM. Similarly, pazopanib potently inhibits stem cell factor??nd PDGF-BB??nduced phosphorylation of c-Kit and PDGFRh in NCI-H526 tumor cells and human foreskin fibroblasts, respectively. Pazopanib selectively inhibits VEGF-induced proliferation of HUVEC with an IC50 of 21.3 nM compared with bFGF-induced HUVEC proliferation with an IC50 of 720.9 nM.[1] Pazopanib (10 μg/mL) inhibits both VEGF-triggered Flt-1 tyrosine phosphorylation (1 and 5 minutes) and activation of downstream signaling molecules (Akt-1 and ERK for 1, 5, and 30 minutes). Pazopanib blocks in vitro MM cell growth, survival, and migration, and inhibits VEGF-induced up-regulation of adhesion molecules on both endothelial and tumor cells.[2] Pazopanib (oral administration of 100 mg/kg), reduces MVD (vessels/mm2) in treated tumors (101 mm2) compared with control tumors (251 mm2) and decreases the proportion of pericyte-covered vessels, assessed by anti??#945;-SMA and anti-NG2 immunostaining, (α-SMA: 0.84 control versus 0.68 pazopanib; NG2: 0.72 control versus 0.26).[3] In Caki-2 (a renal cell carcinoma) xenografts model, 10 mg/kg dose of pazopanib inhibits 77% of tumor growth and 100 mg/kg dose of pazopanib leads to complete cytostasis in mice. In HT29 (colon carcinoma) and NCI-H322 (non??mall-cell lung carcinoma) xenografts models, 100 mg/kg dose of pazopanib almost completely inhibits tumor growth. In A375P (melanoma), PC3 (prostate carcinoma), and BT474 (breast carcinoma) xenografts models, 100 mg/kg dose of pazopanib has a modest inhibition of tumor growth with maximal inhibition reaching 53% to 64%, respectively.[1] In A549 xenografts, 100 mg/kg pazopanib treated tumors has smaller volumes (570 mm3) comparing with control (720 mm3). [3] In a MM xenograft mouse model, 30 mg/kg pazopanib significantly delays tumor growth in treated mice and 100 mg/kg pazopanib almost totally inhibits tumor growth compared with the control group. Furthermore, the mean overall survival (OS) is 20 days in the control cohort versus 41 days and 51 days in groups treated with 30 mg/kg and 100 mg/kg pazopanib, respectively. [2] |
