title: Sunitinib combined with angiotensin-2 type-1 receptor antagonists induces more necrosis: a murine xenograft model of renal cell carcinoma.
abstract: BACKGROUND
  Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects.
  
  
  METHODS
  786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO), the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods.
  
  
  RESULTS
  All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P = 0.06). Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P = 0.038). Central microvascular density decreased (P = 0.0038) as well as circulating VEGF (P = 0.003). There was no significant variation in proliferation or apoptosis markers.
  
  
  CONCLUSIONS
  The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis.
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France ; CHU Rennes, Department of Urology, 35033 Rennes, France ; Rennes University Hospital, 2 rue Henri Le Guilloux, 35033 Rennes Cedex, France.
authors: Grégory
authors: G
authors: Verhoest
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France ; CHU Rennes, Department of Nephrology, 35033 Rennes, France.
authors: Thibault
authors: T
authors: Dolley-Hitze
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France.
authors: Florence
authors: F
authors: Jouan
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France ; CHU Rennes, Department of Cytogenetics, 35033 Rennes, France ; Rennes 1 University, 35043 Rennes, France.
authors: Marc-Antoine
authors: MA
authors: Belaud-Rotureau
authors: Rennes 1 University, 35043 Rennes, France ; CHU Rennes, Department of Clinical Pharmacology, 35033 Rennes, France ; INSERM/Pharmacoepidemiology Team/CIC0203/Biosit, Rennes 1 University, 35043 Rennes, France.
authors: Emmanuel
authors: E
authors: Oger
authors: Rennes 1 University, 35043 Rennes, France ; INSERM/Pharmacoepidemiology Team/CIC0203/Biosit, Rennes 1 University, 35043 Rennes, France.
authors: Audrey
authors: 0000-0002-0049-2397
authors: A
authors: Lavenu
authors: CHU Rennes, Department of Urology, 35033 Rennes, France ; Rennes 1 University, 35043 Rennes, France.
authors: Karim
authors: K
authors: Bensalah
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France ; Rennes 1 University, 35043 Rennes, France.
authors: Yannick
authors: Y
authors: Arlot-Bonnemains
authors: CHU Rennes, Department of Biochemistry, 35033 Rennes, France.
authors: Nicolas
authors: N
authors: Collet
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France ; Rennes 1 University, 35043 Rennes, France ; CHU Rennes, Department of Pathology, 35033 Rennes, France.
authors: Nathalie
authors: N
authors: Rioux-Leclercq
authors: CNRS/UMR 6290/Biosit, Rennes 1 University, 35043 Rennes Cedex, France ; CHU Rennes, Department of Nephrology, 35033 Rennes, France ; Rennes 1 University, 35043 Rennes, France.
authors: Cécile
authors: C
authors: Vigneau
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D000077333:Telmisartan; D023041:Xenograft Model Antitumor Assays
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D007211:Indoles; D011758:Pyrroles; D000077333:Telmisartan; D000077210:Sunitinib