title: Vascular normalization in orthotopic glioblastoma following intravenous treatment with lipid-based nanoparticulate formulations of irinotecan (Irinophore C™), doxorubicin (Caelyx®) or vincristine.
abstract: BACKGROUND
  Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion in the tumor. The present study evaluates how treatment with liposomal formulation of irinotecan (Irinophore C™), and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously.
  
  
  METHODS
  Liposomal vincristine (2 mg/kg), doxorubicin (Caelyx®; 15 mg/kg) and irinotecan (Irinophore C™; 25 mg/kg) were injected intravenously (i.v.; once weekly for 3 weeks) in Rag2M mice bearing U251MG tumors. Tumor blood vessel function was assessed using the marker Hoechst 33342 and by magnetic resonance imaging-measured changes in vascular permeability/flow (Ktrans). Changes in CD31 staining density, basement membrane integrity, pericyte coverage, blood vessel diameter were also assessed.
  
  
  RESULTS
  The three liposomal drugs inhibited tumor growth significantly compared to untreated control (p < 0.05-0.001). The effects on the tumor vasculature were determined 7 days following the last drug dose. There was a 2-3 fold increase in the delivery of Hoechst 33342 observed in subcutaneous tumors (p < 0.001). In contrast there was a 5-10 fold lower level of Hoechst 33342 delivery in the orthotopic model (p < 0.01), with the greatest effect observed following treatment with Irinophore C. Following treatment with Irinophore C, there was a significant reduction in Ktrans in the orthotopic tumors (p < 0.05).
  
  
  CONCLUSIONS
  The results are consistent with a partial restoration of the blood-brain barrier following treatment. Further, treatment with the selected liposomal drugs gave rise to blood vessels that were morphologically more mature and a vascular network that was more evenly distributed. Taken together the results suggest that treatment can lead to normalization of GBM blood vessel the structure and function. An in vitro assay designed to assess the effects of extended drug exposure on endothelial cells showed that selective cytotoxic activity against proliferating endothelial cells could explain the effects of liposomal formulations on the angiogenic tumor vasculature.
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10thAvenue, Vancouver, BC V5Z 1L3, Canada. mverreau@bccrc.ca
authors.forename: Maite
authors.initials: M
authors.lastname: Verreault
authors.forename: Dita
authors.initials: D
authors.lastname: Strutt
authors.forename: Dana
authors.initials: D
authors.lastname: Masin
authors.forename: Malathi
authors.initials: M
authors.lastname: Anantha
authors.forename: Andrew
authors.initials: A
authors.lastname: Yung
authors.forename: Piotr
authors.initials: P
authors.lastname: Kozlowski
authors.forename: Dawn
authors.initials: D
authors.lastname: Waterhouse
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.forename: Donald T
authors.initials: DT
authors.lastname: Yapp
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage; D047368:Tumor Burden; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D008081:Liposomes; C499308:Rag2 protein, mouse; D014750:Vincristine; D000077146:Irinotecan; D004317:Doxorubicin; D002166:Camptothecin