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.