title: Rapamycin-induced tumor vasculature remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation.
abstract: OBJECTIVE
  Rapamycin inhibits vascular endothelial growth factor expression. Vascular endothelial growth factor is a tumor-elaborated protein that stimulates neovascularization. This inhibition can cause transient "normalization" of the generally dysfunctional tumor vasculature, resulting in improved tumor perfusion and oxygenation. We hypothesized that this may potentiate the antitumor effects of adjuvant ionizing radiation.
  
  
  METHODS
  Mice bearing orthotopic Rh30 alveolar rhabdomyosarcomas were treated with rapamycin (5 mg/kg intraperitoneally daily ×5). Tumors were then evaluated for changes in intratumoral oxygenation, perfusion, vessel permeability, and microvessel density. Additional tumor-bearing mice were treated with 5 doses of rapamycin, irradiation (4 Gy), or 5 doses of rapamycin with irradiation administered on the first or sixth day of rapamycin treatment.
  
  
  RESULTS
  Although tumor vessel permeability changed only minimally, microvessel density decreased (3153 ± 932 vs 20,477 ± 3717.9 pixels per high-power field), whereas intratumoral oxygenation increased significantly (0.0385 ± 0.0141 vs 0.0043 ± 0.0023 mm Hg/mm(3)) after 5 doses of rapamycin. Contrast-enhanced ultrasound demonstrated a significantly increased rate of change of signal intensity after 5 days of rapamycin, suggesting improved intratumoral perfusion. Tumor volume 14 days after treatment was smallest in mice treated with the combination of rapamycin given before irradiation.
  
  
  CONCLUSIONS
  Combination therapy with rapamycin given before irradiation to normalize the tumor vasculature, thereby improving tumor oxygenation, increased the sensitivity of alveolar rhabdomyosarcoma xenografts to adjuvant irradiation.
authors.affiliation: Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Adrianne L
authors.initials: AL
authors.lastname: Myers
authors.forename: W Shannon
authors.initials: WS
authors.lastname: Orr
authors.forename: Jason W
authors.initials: JW
authors.lastname: Denbo
authors.forename: Catherine Y
authors.initials: CY
authors.lastname: Ng
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhou
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Spence
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011839:Radiation, Ionizing; D018232:Rhabdomyosarcoma, Alveolar / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D020123:Sirolimus / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus