title: Myelosuppression of thrombocytes and monocytes is associated with a lack of synergy between chemotherapy and anti-VEGF treatment.
abstract: OBJECTIVE
  Chemotherapeutic agents that have shown improved patient outcome when combined with anti-vascular endothelial growth factor (VEGF) therapy were recently identified to induce the mobilization of proangiogenic Tie-2-expressing monocytes (TEMs) and endothelial progenitor cells (EPCs) by platelet release of stromal cell-derived factor 1α (SDF-1α). VEGF blockade was found to counteract cell mobilization. We aimed to determine why agents like gemcitabine do not elicit TEM and EPC recruitment and may therefore lack synergy with anti-VEGF therapy.
  
  
  METHODS
  Locally advanced pancreatic cancer patients (n = 20) were monitored during 16 weeks of neoadjuvant therapy. Treatment was based on gemcitabine with or without the addition of bevacizumab. Blood levels of proangiogenic cell populations and angiogenesis factors were determined in 2-week intervals.
  
  
  RESULTS
  The lack of EPC mobilization during gemcitabine therapy was associated with severe thrombocytopenia and reduced SDF-1α blood concentrations. Furthermore, myelosuppression by gemcitabine correlated significantly with loss of TEMs. With respect to angiogenic factors stored and released by platelets, plasma levels of the angiogenesis inhibitor thrombospondin 1 (TSP-1) were selectively decreased and correlated significantly with thrombocytopenia in response to gemcitabine therapy.
  
  
  CONCLUSIONS
  A thorough literature screen identified thrombocytopenia as a common feature of chemotherapeutic agents that lack synergy with anti-VEGF treatment. Our results on gemcitabine therapy indicate that myelosuppression (in particular, with respect to thrombocytes and monocytes) interferes with the mobilization of proangiogenic cell types targeted by bevacizumab and may further counteract antiangiogenic therapy by substantially reducing the angiogenesis inhibitor TSP-1.
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Starlinger
authors.forename: Philipp
authors.initials: P
authors.lastname: Brugger
authors.forename: Dominic
authors.initials: D
authors.lastname: Schauer
authors.forename: Silvia
authors.initials: S
authors.lastname: Sommerfeldt
authors.forename: Dietmar
authors.initials: D
authors.lastname: Tamandl
authors.forename: Irene
authors.initials: I
authors.lastname: Kuehrer
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Schoppmann
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.forename: Christine
authors.initials: C
authors.lastname: Brostjan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000097:blood / Q000172:deficiency; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020360:Neoadjuvant Therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013921:Thrombocytopenia; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054377:Chemokine CXCL12; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000068258:Bevacizumab; D000093542:Gemcitabine