Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-derived growth factors suppresses tumor growth and enhances tumor radiation response.
We have investigated the effect of simultaneous inhibition of multiple angiogenic growth factor signaling pathways on tumor growth, tumor blood perfusion, and radiation-induced tumor-growth delay using SU6668, an inhibitor of the receptor-tyrosine kinase activity of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). The SCK mammary carcinoma, FSaII fibrosarcoma, and CFPAC human pancreatic carcinoma were grown s.c. in the hind leg of A/J mice, C3H mice, and Balb/cAnNCrl-nuBr nude mice, respectively. Daily i.p. injection of 100 mg/kg of SU6668 markedly suppressed the growth of these three tumor types. SU6668 also markedly prolonged the survival time of host mice bearing SCK tumors, which appeared to be caused by a reduction of metastatic tumor growth in the lung. There was little or no change in normal tissue blood perfusion, whereas in SCK tumors the perfusion decreased by 50% at 1 h after a single i.p. injection of SU6668, slightly recovered at 4 h, and completely recovered by 8 h. Interestingly, the tumor blood flow was significantly increased above the baseline level 24 h after SU6668 injection. After extended daily i.p. injections of SU6668, the tumor blood flow in all of the three tumor types studied was markedly decreased compared with control. The observed effects of this drug on tumor blood perfusion may partially explain the effectiveness of the compound in suppressing tumor growth and extending survival of tumor-bearing mice. We also observed that daily SU6668 administration and a single dose of 15 Gy of X-irradiation was significantly more effective than either treatment alone in suppressing tumor growth. Our results suggest that SU6668 increased the radiosensitivity of tumor blood vessels. We conclude that SU6668 is a potent therapeutic agent potentially useful to suppress tumor growth and enhance the response of tumors to radiotherapy.
Griffin
Robert J
RJ
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota 55455 [R. J. G., B. W. W., H. P., C. W. S.], and Sugen, Inc, South San Francisco, California 94080 [R. W., J. M. C.].
Williams
Brent W
BW
Wild
Robert
R
Cherrington
Julie M
JM
Park
Heonjoo
H
Song
Chang W
CW
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D017024:Chemotherapy, Adjuvant; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D000078183:Oxindoles; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D011422:Propionates; D011758:Pyrroles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor
D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; C412603:orantinib; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor