Biological evidence for dual antiangiogenic-antiaromatase activity of the VEGFR inhibitor PTK787/ZK222584 in vivo.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

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: Susana Banerjee, Roger A'Hern, Simone Detre, Amanda J Littlewood-Evans, Dean B Evans, Mitchell Dowsett, Lesley-Ann Martin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 16 Pg. 4178-87 (Aug 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20682704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Aromatase Inhibitors
• Nitriles
• Phthalazines
• Pyridines
• Receptors, Estrogen
• Triazoles
• vatalanib
• Letrozole
• Aromatase
• Receptors, Vascular Endothelial Growth Factor

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Aromatase (metabolism)
• Aromatase Inhibitors (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Immunohistochemistry
• Letrozole
• Mammary Neoplasms, Experimental (drug therapy, metabolism)
• Mice
• Mice, Nude
• Neovascularization, Pathologic (drug therapy)
• Nitriles (pharmacology)
• Phthalazines (pharmacology)
• Pyridines (pharmacology)
• Receptors, Estrogen (biosynthesis)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Triazoles (pharmacology)
• Xenograft Model Antitumor Assays