Abstract
BackgroundChemotherapy 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.MethodsLiposomal 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.ResultsThe 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).ConclusionThe 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.
Highlights
Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion in the tumor
A decrease in number of cell nuclei per area with a concomitant increase in connective tissue was observed by examination of the Hematoxylin and Eosin (H&E) stained sections in tumors from mice treated with Irinophore CTM
In aggregate, data from this study indicates that liposomal formulations of irinotecan, doxorubicin and vincristine exert anti-angiogenic effects, as measured by endpoints assessing increases in mature blood vessels and improved vascular function
Summary
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 CTM), and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously. Strategies which improve vascular function in GBM tumors should improve the delivery of other drugs capable of crossing the blood brain barrier and this should be associated with an increase in therapeutic activity. (subcutaneous) colorectal tumors (HT-29) exhibited more functional tumor blood vessels, reduced hypoxia, and increased tumor perfusion. These changes in tumor vasculature were associated with increased tumor uptake of doxorubicin and 5-FU given intravenously [8]. The latter data were consistent with the idea that the tumor vasculature in the treated tumors acquires a more “normallike” function; an effect of anti-angiogenic therapies described as ‘normalization’ [9,10]
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