Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584In 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 17β-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. Clin Cancer Res; 16(16); 4178-87. ©2010 AACR.

Anastrozole and celecoxib for endometriosis treatment, good to keep them apart?

“…In accordance with our results, treatment with another selective COX-2 inhibitor had been reported to reduce microvessel density in a SCID mouse model of endometriosis (Ozawa et al 2006). Furthermore, another study in a xenograft model of breast cancer showed that the use of letrozole, another aromatase inhibitor, did not reduce the number of CD31-stained vessels, another well-established vascularization marker (Banerjee et al 2010).…”

Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival

“…Increased serum VEGF levels have been also considered as a marker of metastatic uveal melanoma [30]. This observation becomes of particular importance after the development of specific inhibitors of VEGFR2/KDR receptors, already tested in phase II clinical trials [31][32][33]. Such targeted therapeutic policy may be proved useful in the treatment of malignant melanomas with HIF2a activated VEGF/receptor autocrine function.…”

Synthesis and biological evaluation of novel anthranilamide derivatives as anticancer agents

“…PTK787 (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine, Figure 1), a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1, 2, 3 (VEGFR-1, 2, 3), platelet-derived growth factor receptor (PDGFR) and stem cell growth factor receptor (SCFR, also known as C-Kit) with anti-tumor activity, has undergone clinical trials for the treatment of breast, colorectal and other cancers (3)(4)(5). P. Furet et al reasoned that an anthranilamide moiety ( Figure 1) presenting a strong intramolecular hydrogen bond between the amine and keto functionalities to form a pseudo six membered ring could mimic the phthalazine ring of PTK787 (6).…”