title: Combination of vessel-targeting agents and fractionated radiation therapy: the role of the SDF-1/CXCR4 pathway.
abstract: OBJECTIVE
  To investigate vascular responses during fractionated radiation therapy (F-RT) and the effects of targeting pericytes or bone marrow-derived cells (BMDCs) on the efficacy of F-RT.
  
  
  METHODS
  Murine prostate TRAMP-C1 tumors were grown in control mice or mice transplanted with green fluorescent protein-tagged bone marrow (GFP-BM), and irradiated with 60 Gy in 15 fractions. Mice were also treated with gefitinib (an epidermal growth factor receptor inhibitor) or AMD3100 (a CXCR4 antagonist) to examine the effects of combination treatment. The responses of tumor vasculatures to these treatments and changes of tumor microenvironment were assessed.
  
  
  RESULTS
  After F-RT, the tumor microvascular density (MVD) was reduced; however, the surviving vessels were dilated, incorporated with GFP-positive cells, tightly adhered to pericytes, and well perfused with Hoechst 33342, suggesting a more mature structure formed primarily via vasculogenesis. Although the gefitinib+F-RT combination affected the vascular structure by dissociating pericytes from the vascular wall, it did not further delay tumor growth. These tumors had higher MVD and better vascular perfusion function, leading to less hypoxia and tumor necrosis. By contrast, the AMD3100+F-RT combination significantly enhanced tumor growth delay more than F-RT alone, and these tumors had lower MVD and poorer vascular perfusion function, resulting in increased hypoxia. These tumor vessels were rarely covered by pericytes and free of GFP-positive cells.
  
  
  CONCLUSIONS
  Vasculogenesis is a major mechanism for tumor vessel survival during F-RT. Complex interactions occur between vessel-targeting agents and F-RT, and a synergistic effect may not always exist. To enhance F-RT, using CXCR4 inhibitor to block BM cell influx and the vasculogenesis process is a better strategy than targeting pericytes by epidermal growth factor receptor inhibitor.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Fang-Hsin
authors.initials: FH
authors.lastname: Chen
authors.forename: Sheng-Yung
authors.initials: SY
authors.lastname: Fu
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Yang
authors.forename: Chun-Chieh
authors.initials: CC
authors.lastname: Wang
authors.forename: Chi-Shiun
authors.initials: CS
authors.lastname: Chiang
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Hong
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001562:Benzimidazoles; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000502:physiology*; D003131:Combined Modality Therapy / Q000379:methods; D000080027:Cyclams; D019583:Dose Fractionation, Radiation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D049452:Green Fluorescent Proteins; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D049408:Luminescent Agents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000532:radiotherapy; D011799:Quinazolines / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D049408:Luminescent Agents; D011799:Quinazolines; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors; C017807:bisbenzimide ethoxide trihydrochloride; D000077156:Gefitinib; C088327:plerixafor