ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration

Cancer Res. 2002 Aug 15;62(16):4645-55.


ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine]is a potent, p.o. active, low molecular weight inhibitor of kinase insert domain-containing receptor [KDR/vascular endothelial growth factor receptor (VEGFR) 2] tyrosine kinase activity (IC(50) = 40 nM). This compound has some additional activity versus the tyrosine kinase activity of fms-like tyrosine kinase 4 (VEGFR3;IC(50) = 110 nM) and epidermal growth factor receptor (EGFR/HER1; IC(50) = 500 nM) and yet demonstrates selectivity against a range of other tyrosine and serine-threonine kinases. The activity of ZD6474 versus KDR tyrosine kinase translates into potent inhibition of vascular endothelial growth factor-A (VEGF)-stimulated endothelial cell (human umbilical vein endothelial cell) proliferation in vitro (IC(50) = 60 nM). Selective inhibition of VEGF signaling has been demonstrated in vivo in a growth factor-induced hypotension model in anesthetized rat: administration of ZD6474 (2.5 mg/kg, i.v.) reversed a hypotensive change induced by VEGF (by 63%) but did not significantly affect that induced by basic fibroblast growth factor. Once-daily oral administration of ZD6474 to growing rats for 14 days produced a dose-dependent increase in the femoro-tibial epiphyseal growth plate zone of hypertrophy, which is consistent with inhibition of VEGF signaling and angiogenesis in vivo. Administration of 50 mg/kg/day ZD6474 (once-daily, p.o.) to athymic mice with intradermally implanted A549 tumor cells also inhibited tumor-induced neovascularization significantly (63% inhibition after 5 days; P < 0.001). Oral administration of ZD6474 to athymic mice bearing established (0.15-0.47 cm(3)), histologically distinct (lung, prostate, breast, ovarian, colon, or vulval) human tumor xenografts or after implantation of aggressive syngeneic rodent tumors (lung, melanoma) in immunocompetent mice, produced a dose-dependent inhibition of tumor growth in all cases. Statistically significant antitumor activity was evident in each model with at least 25 mg/kg ZD6474 once daily (P < 0.05, one-tailed t test). Histological analysis of Calu-6 tumors treated with 50 mg/kg/day ZD6474 for 24 days showed a significant reduction (>70%) in CD31 (endothelial cell) staining in nonnecrotic regions. ZD6474 also restrained growth of much larger (0.9 cm(3) volume) Calu-6 lung tumor xenografts and induced profound regression in established PC-3 prostate tumors of 1.4 cm(3) volume. ZD6474 is currently in Phase I clinical development as a once-daily oral therapy in patients with advanced cancer.

MeSH terms

  • Administration, Oral
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Division / drug effects
  • Endothelial Growth Factors / antagonists & inhibitors*
  • Endothelial Growth Factors / physiology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Lymphokines / antagonists & inhibitors*
  • Lymphokines / physiology
  • Male
  • Mice
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic / drug therapy
  • Piperidines / pharmacology*
  • Quinazolines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptors, Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Lymphokines
  • Piperidines
  • Quinazolines
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • vandetanib