Improved effect of an antiangiogenic tyrosine kinase inhibitor (SU5416) by combinations with fractionated radiotherapy or low molecular weight heparin.
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.
Lund
Eva L
EL
Institute of Molecular Pathology, University of Copenhagen, Copenhagen DK-2100, Denmark.
Olsen
Minna W B
MW
Lipson
Kenneth E
KE
McMahon
Gerald
G
Howlett
Anthony R
AR
Kristjansen
Paul E G
PE
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
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