title: The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation.
abstract: Angiogenesis is critical for tumor development, growth and metastasis. The vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) and their tyrosine kinase receptors are major regulators of angiogenesis. Radiation induces the production of VEGF, FGF and PDGF in many tumor cells. We hypothesized that inhibition of the function of these growth factors could inhibit tumor angiogenesis and thereby enhance the efficacy of radiation therapy. To test this hypothesis, we used the small molecule inhibitors SU5416 (an inhibitor for Vegf receptor) and SU6668 (an inhibitor for Vegf, Fgf and Pdgf receptors) alone and in combination with fractionated irradiation to treat C3H mice bearing SCC VII carcinomas. The SCC VII tumors express Vegf, Fgf2 (also known as bFGF), Pdgf and their associated receptors. Animals were given either SU5416 or SU6668 daily before or after irradiation (2 Gy per fraction per day for 5 days). The results from these experiments demonstrate that administration of either SU5416 or SU6668 without radiation delayed tumor growth. Administration of SU5416 at a dose of 25 mg/kg per day (the maximum tolerated effective dose) inhibited tumor growth by 17.9% on day 7 (P < 0.05 compared to untreated control mice) and produced an average tumor growth delay time of 0.5-2.0 days. When combined with fractionated irradiation, administration of SU5416 increased the inhibition of tumor growth to 50-53% on day 7 and the tumor growth delay time to 5.7-6.5 days (P < 0.001 compared with SU5416 alone; P < or = 0.05 compared with radiation alone). SU6668 alone inhibited tumor growth in a dose-dependent manner. Administration of SU6668 at a dose of 75 mg/kg per day (a suboptimal dose) inhibited tumor growth by 36% on day 7 and produced an average tumor growth delay time of 3.3 +/- 1.4 days. The combination of SU6668 with fractionated radiation increased inhibition of tumor growth to 66-70% and the tumor growth delay time from 3.3 days to 11.9 days (P < or = 0.001 compared with either radiation alone or SU6668 alone). Administration of these agents before or after irradiation produced similar results (P = 0.40 for SU5416; P = 0.98 for SU6668). SU5416 or SU6668 alone or in combination with radiation was very well tolerated with little or no toxicity. These results suggest that inhibition of Vegf, Fgf and Pdgf receptor function by SU5416 and SU6668 can enhance the efficacy of irradiation. The targeting of multiple tyrosine kinase receptors by SU6668 is more effective than inhibition of the Vegf receptor alone by SU5416 for the enhancement of tumor cell killing by fractionated irradiation.
authors.affiliation: Department of Radiation Oncology, Stanford University Medical Center, Stanford, California 94305-5105, USA.
authors.forename: Shoucheng
authors.initials: S
authors.lastname: Ning
authors.forename: Douglas
authors.initials: D
authors.lastname: Laird
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cherrington
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Knox
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D019583:Dose Fractionation, Radiation; D004354:Drug Screening Assays, Antitumor; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics; D011422:Propionates; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D011867:Radioisotope Teletherapy; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D013047:Specific Pathogen-Free Organisms; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D007211:Indoles; D008222:Lymphokines; D009363:Neoplasm Proteins; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor; D011422:Propionates; D011758:Pyrroles; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; C416849:SU 5614; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C412603:orantinib; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor