title: Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients.
abstract: OBJECTIVE
  To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy.
  
  
  METHODS
  Phase II trials of VEGF pathway-targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy. Primary tumor tissues were obtained and assessed for angiogenesis parameters. Results were compared with similar analyses on untreated tumors.
  
  
  RESULTS
  Sunitinib or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor. Also, an increase in vascular pericyte coverage was found in sunitinib-pretreated tumors, consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues, among which VEGFR-1 and VEGFR-2, angiopoietin-1 and angiopoietin-2 and platelet-derived growth factor-B. In addition, apoptosis in tumor and endothelial cells was induced. Interestingly, in sunitinib-pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab-pretreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment.
  
  
  CONCLUSIONS
  This study describes, for the first time, the angiostatic response in human primary renal cancers at the tissue level upon treatment with VEGF-targeted therapy. Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation. The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors.
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Mans
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Annemarie M A
authors.initials: AMA
authors.lastname: de Graaf
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Nowak-Sliwinska
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Céline L M M
authors.initials: CLMM
authors.lastname: de Hoog
authors.affiliation: Division of Immunology, Antoni van Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Trees A M
authors.initials: TAM
authors.lastname: de Jong
authors.affiliation: Division of Immunology, Antoni van Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Florry A
authors.initials: FA
authors.lastname: Vyth-Dreese
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Judy R
authors.initials: JR
authors.lastname: van Beijnum
authors.affiliation: Department of Urology, Antoni van Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Bex
authors.affiliation: Department of Genitourinary Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D055806:Microvessels / Q000187:drug effects; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage*; D012189:Retrospective Studies; D000077210:Sunitinib
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011758:Pyrroles; D000068258:Bevacizumab; D000077210:Sunitinib