SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models.
Receptor tyrosine kinase activation contributes to cell viability during cytotoxic therapy. The novel broad spectrum receptor tyrosine kinase inhibitor, SU11248, inhibits vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-kit, and fetal liver tyrosine kinase 3. In this study, we maintained SU11248 plasma levels beyond the completion of radiotherapy to determine whether tumor regrowth can be delayed. The antiangiogenic effects of SU11248 were demonstrated using human umbilical vein endothelial cells in vitro. Apoptosis increased and clonogenic survival decreased when SU11248 was used in combination with radiation from 0 to 6 Gy on endothelial cells. In vivo tumor growth delay was increased in C57B6J mice with Lewis lung carcinoma or glioblastoma multiform (GL261) hind limb tumors. Mice were treated with daily i.p. injections (40 mg/kg) of SU11248 during 7 days of radiation treatment (21 Gy). Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared with either treatment alone. Concomitant reduction in vasculature was confirmed using the dorsal vascular window model. The vascular length established using images taken from a consistent quadrant in the window show the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU11248 maintenance administration beyond the completion of radiotherapy results in prolongation of tumor control. In summary, SU11248 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. Moreover, inhibition of angiogenesis well beyond radiation therapy may be a promising treatment paradigm for refractory human neoplasms.
Schueneman
Aaron J
AJ
Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Himmelfarb
Eric
E
Geng
Ling
L
Tan
Jiahua
J
Donnelly
Edwin
E
Mendel
Dirk
D
McMahon
Gerald
G
Hallahan
Dennis E
DE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077210:Sunitinib
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib