Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models

• Published in: Cancer chemotherapy and pharmacology 2007-04, Vol.59 (5), p.561-574
• Main Authors: CHANG, Yong S, ADNANE, Jalila, WILKIE, Dean, CARTER, Christopher A, TAYLOR, Ian C. A, LYNCH, Mark, WILHELM, Scott, TRAIL, Pamela A, LEVY, Joan, HENDERSON, Arris, DAHAI XUE, BORTOLON, Elizabeth, ICHETOVKIN, Marina, CHEN, Charles, MCNABOLA, Angela
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Adenocarcinoma, Clear Cell - blood supply; Adenocarcinoma, Clear Cell - drug therapy; Adenocarcinoma, Clear Cell - pathology; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Benzenesulfonates - therapeutic use; Biological and medical sciences; Capillaries - pathology; Cell Line, Tumor; Female; Humans; Hypoxia - chemically induced; Hypoxia - pathology; Immunohistochemistry; In Situ Nick-End Labeling; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Kidney Neoplasms - pathology; Kidneys; Medical sciences; Mice; Mice, Nude; Nephrology. Urinary tract diseases; Niacinamide - analogs & derivatives; Pharmacology. Drug treatments; Phenylurea Compounds; Platelet Endothelial Cell Adhesion Molecule-1 - immunology; Pyridines - therapeutic use; Regional Blood Flow - drug effects; Tumors of the urinary system; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-006-0393-4

New research findings have revealed a key role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in clear cell renal carcinoma (RCC) which is a highly vascularized and treatment-resistant tumor. Sorafenib (BAY 43-9006, Nexavar) is a multi-kinase inhibitor which targets receptor tyrosine and serine/threonine kinases involved in tumor progression and tumor angiogenesis. The effect of sorafenib on tumor growth and tumor histology was assessed in both ectopic and orthotopic mouse models of RCC. Sorafenib was administered orally to mice bearing subcutaneous (SC, ectopic) or sub-renal capsule (SRC, orthotopic) tumors of murine (Renca) or human (786-O) RCC. Treatment efficacy was determined by measurements of tumor volume and tumor growth delay. In mechanism of action studies, using the 786-O and Renca RCC tumor models, the effect of sorafenib was assessed after dosing for 3 or 5 days in the SC models and 21 days in the SRC models. Inhibition of tumor angiogenesis was assessed by measuring level of CD31 and alpha-smooth muscle actin (alphaSMA) staining by immunohistochemistry (IHC). The effect of sorafenib on MAPK signaling, cell cycle progression and cell proliferation was also assessed by IHC by measuring levels of phospho-ERK, phospho-histone H3 and Ki-67 staining, respectively. The extent of tumor apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. Finally, the effects of sorafenib on tumor hypoxia was assessed in 786-O SC model by injecting mice intravenously with pimonidazole hydrochloride 1 h before tumor collection and tumor sections were stained with a FITC-conjugated Hypoxyprobe antibody. Sorafenib produced significant tumor growth inhibition (TGI) and a reduction in tumor vasculature of both ectopic and orthotopic Renca and 786-O tumors, at a dose as low as 15 mg/kg when administered daily. Inhibition of tumor vasculature was observed as early as 3 days post-treatment, and this inhibition of angiogenesis correlated with increased level of tumor apoptosis (TUNEL-positive) and central necrosis. Consistent with these results, a significant increase in tumor hypoxia was also observed 3 days post-treatment in 786-O SC model. However, no significant effect of sorafenib on phospho-ERK, phospho-histone H3 or Ki-67 levels in either RCC tumor model was observed. Our results show the ability of sorafenib to potently inhibit the growth of both ectopically- and orthotopically-impl