title: Biological evidence for dual antiangiogenic-antiaromatase activity of the VEGFR inhibitor PTK787/ZK222584 in vivo.
abstract: OBJECTIVE
  Targeting vascular endothelial growth factor (VEGF) and estrogen receptor signaling pathways concomitantly may enhance benefit in estrogen receptor-positive breast cancer. We had shown previously that the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) is a competitive aromatase inhibitor in vitro. Here we investigated (a) whether PTK/ZK shows both antiangiogenic and antiaromatase inhibitory properties in vivo, and (b) whether the combination of PTK/ZK and letrozole is superior to letrozole alone.
  
  
  METHODS
  Estrogen-dependent human breast cancer cells engineered to express aromatase (MCF7 AROM 1 and BT474 AROM) were used. Mice were treated with vehicle, PTK/ZK (25, 50, or 100 mg/kg), letrozole, or PTK/ZK in combination with letrozole.
  
  
  RESULTS
  In MCF7 AROM 1 tumors, all treatments induced growth suppression and were associated with a reduction in cell turnover index, a composite measurement of both proliferation and apoptosis. PTK/ZK significantly reduced vessel density. Whereas letrozole caused tumor regression, PTK/ZK stabilized tumor volumes. The growth suppressive and antiangiogenic effects of PTK/ZK were confirmed in BT474 AROM xenografts. The addition of PTK/ZK did not enhance the growth-suppressive effects of letrozole. However, PTK/ZK decreased progesterone receptor (PgR) and TFF1 expression and uterine weight, indicating that PTK/ZK decreases 17beta-estradiol (E2) signaling in vivo.
  
  
  CONCLUSIONS
  The VEGF receptor inhibitor PTK/ZK showed effects on E2-dependent gene expression consistent with aromatase inhibition as well as antiangiogenesis in xenograft models of breast cancer. The combination with letrozole was not superior to letrozole alone. Overall, these results provide further support for a potential therapeutic approach of dual inhibition of VEGF and E2 signaling using a single agent.
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Banerjee
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Littlewood-Evans
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: Mitchell
authors.initials: M
authors.lastname: Dowsett
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009570:Nitriles / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D010793:Phthalazines; D011725:Pyridines; D011960:Receptors, Estrogen; D014230:Triazoles; C404768:vatalanib; D000077289:Letrozole; D001141:Aromatase; D040262:Receptors, Vascular Endothelial Growth Factor