title: Improved effect of an antiangiogenic tyrosine kinase inhibitor (SU5416) by combinations with fractionated radiotherapy or low molecular weight heparin.
abstract: The effect of combining SU5416 with fractionated radiotherapy or with low molecular weight (LMW) heparin (dalteparin) was studied in U87 human glioblastoma xenografts in nude mice. SU5416 is antiangiogenic by a specific inhibition of the vascular endothelial growth factor receptor 2 (VEGFR-2), and heparins are assumed to bind VEGF. Both SU5416 (100 mg/kg every second day in 5 days) and 3 Gyx5 produced moderate, yet significant, growth inhibition. Tumors treated with concomitant irradiation and short-term SU5416 maintained a lower growth rate during regrowth than the other treatment groups (P=.007). Dalteparin (1000 IE/kg subcutaneously once a day) had no growth-inhibitory effect on its own, but when this LMW heparin was added to the SU5416 schedule, a significantly enhanced growth inhibition was obtained. VEGF protein content in tumors was not significantly altered by SU5416, but a significant decrease in VEGF levels was found in tumors treated with concomitant dalteparin and SU5416 compared with controls (P=.03). We conclude that: 1) an additive growth-inhibitory effect is obtained by combining SU5416 and fractionated radiotherapy; and 2) LMW heparin (dalteparin), in combination with SU5416, decreases the level of VEGF in tumors and increases the growth-inhibitory effect of SU5416.
authors.affiliation: Institute of Molecular Pathology, University of Copenhagen, Copenhagen DK-2100, Denmark.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Lund
authors.forename: Minna W B
authors.initials: MW
authors.lastname: Olsen
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.forename: Gerald
authors.initials: G
authors.lastname: McMahon
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Howlett
authors.forename: Paul E G
authors.initials: PE
authors.lastname: Kristjansen
mesh_terms: D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D017985:Dalteparin / Q000494:pharmacology; D019583:Dose Fractionation, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005343:Fibrinolytic Agents / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D006493:Heparin; D011505:Protein-Tyrosine Kinases; D017985:Dalteparin