title: (99)mTc-(CO)(3) His-annexin A5 micro-SPECT demonstrates increased cell death by irinotecan during the vascular normalization window caused by bevacizumab.
abstract: Colorectal tumors are dependent on angiogenesis for growth, and vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Antiangiogenic drugs can induce a transient normalization of the tumor vasculature with improved delivery of coadministered chemotherapy. The efficacy of antihuman VEGF antibody (bevacizumab) with or without irinotecan was evaluated in a colorectal cancer xenograft using (99m)Tc-(CO)(3) His-annexin A5.
  
  
  METHODS
  Colo205-bearing mice were treated with a single dose of bevacizumab (5 mg/kg) during 2, 4, or 6 d. Microvessel density, pericyte coverage (α-smooth-muscle actin immunostaining), collagen-covered tumor vessels (Masson trichrome staining), and tumor hypoxic fraction (pimonidazole staining) were determined at the 3 different time points after treatment with bevacizumab. To investigate the possible synergistic effects of combination therapy with bevacizumab and irinotecan, Colo205-bearing mice were treated with a single dose of bevacizumab 2, 4, or 6 d before administration of a single dose of irinotecan (100 mg/kg) or 0.9% NaCl. The apoptosis-detecting radiotracer (99m)Tc-(CO)(3) His-annexin A5 was injected (18.5 MBq) in mice 12, 24, and 48 h after the start of the irinotecan or NaCl treatment, and micro-SPECT was subsequently performed 3.5 h after injection of the radiotracer. Results were correlated to histologic analysis for apoptosis (caspase-3 activation).
  
  
  RESULTS
  Four days after bevacizumab administration, microvessel density decreased significantly, and α-smooth-muscle actin and collagen-covered vessels, compared with control tumors, were increased, suggesting normalization of the tumor vasculature. Hypoxic fraction was slightly reduced 4 d after treatment with bevacizumab. SPECT analyses demonstrated a significant increase in tumoral (99m)Tc-(CO)(3) His-annexin A5 uptake 4 d after bevacizumab treatment and 24 h after irinotecan administration (232.78 ± 24.82 percentage injected dose/tumor weight [g]/body weight [kg], P < 0.05), compared with each monotherapy, indicating a synergistic effect of both therapies.
  
  
  CONCLUSIONS
  (99m)Tc-(CO)(3) His-annexin A5 micro-SPECT demonstrates increased antitumor activity of irinotecan during the transient vascular normalization period caused by bevacizumab. Our data outline the importance of timing of combined anti-VEGF treatment with chemotherapy.
authors: Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium. christel.vangestel@uza.be
authors: Christel
authors: C
authors: Vangestel
authors: Christophe
authors: C
authors: Van de Wiele
authors: Nancy
authors: N
authors: Van Damme
authors: Steven
authors: S
authors: Staelens
authors: Patrick
authors: P
authors: Pauwels
authors: Chris P M
authors: CP
authors: Reutelingsperger
authors: Marc
authors: M
authors: Peeters
mesh_terms: D000199:Actins / Q000235:genetics; D042683:Angiopoietin-1 / Q000235:genetics; D000818:Animals; D017304:Annexin A5; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000068258:Bevacizumab; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D005260:Female; D000077146:Irinotecan; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D015609:Organotechnetium Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D015899:Tomography, Emission-Computed, Single-Photon; D014158:Transcription, Genetic / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C568748:(99)mTc-(CO)(3) His-annexin A5; D000199:Actins; D042683:Angiopoietin-1; D017304:Annexin A5; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015609:Organotechnetium Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077146:Irinotecan; D053148:Caspase 3; D002166:Camptothecin